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Although men’s incarceration rates have declined in the United States, women’s have stayed steady and even risen in some areas. At the same time, courts have increased their use of monetary sanctions, especially for low-level offenses. We propose that women’s incarceration trends can be partially explained by county dependence on monetary sanctions as a source of revenue. We suggest that monetary sanctions expose female defendants to processes that increase their likelihood of incarceration, especially in counties more reliant on monetary sanctions as a source of revenue, and where women’s poverty rates are high. Using data from Washington State, we find county dependence on monetary sanctions is positively associated with rates of women sentenced to incarceration. Although rural counties’ rates are higher, they depend on monetary sanctions no more than nonrural counties do.

The number and distribution of recessive alleles in the population for various diseases are not known at genome-wide-scale. Based on 6447 exome-sequences of healthy, genetically-unrelated Europeans of two distinct ancestries, we estimate that every individual is a carrier of at least 2 pathogenic variants in currently known autosomal recessive (AR) genes, and that 0.8-1% of European couples are at-risk of having a child affected with a severe AR genetic disorder. This risk is 16.5-fold higher for first cousins, but is significantly more increased for skeletal disorders and intellectual disabilities due to their distinct genetic architecture.

Students' perceptions of challenges in biology influence performance outcomes, experiences, and persistence in science. Identifying sources of student struggle can assist efforts to support students as they overcome challenges in their undergraduate educations. In this study, we characterized student experiences of struggle by 1) quantifying which external factors relate to perceptions of encountering and overcoming struggle in introductory biology and 2) identifying factors to which students attribute their struggle in biology. We found a significant effect of Course, Instructor, and Incoming Preparation on student struggle, in which students with lower Incoming Preparation were more likely to report struggle and the inability to overcome struggle. We also observed significant differences in performance outcomes between students who did and did not encounter struggle and between students who did and did not overcome their struggle. Using inductive coding, we categorized student responses outlining causes of struggle, and using axial coding, we further categorized these as internally or externally attributed factors. External sources (i.e., Prior Biology, COVID-19, External Resources, Classroom Factors) were more commonly cited as the reason(s) students did or did not struggle. We conclude with recommendations for instructors, highlighting equitable teaching strategies and practices.

The Iron and Classical Ages in the Near East were marked by population expansions carrying cultural transformations that shaped human history, but the genetic impact of these events on the people who lived through them is little-known. Here, we sequenced the whole genomes of 19 individuals who each lived during one of four time periods between 800 BCE and 200 CE in Beirut on the Eastern Mediterranean coast at the center of the ancient world's great civilizations. We combined these data with published data to traverse eight archaeological periods and observed any genetic changes as they arose. During the Iron Age (∼1000 BCE), people with Anatolian and South-East European ancestry admixed with people in the Near East. The region was then conquered by the Persians (539 BCE), who facilitated movement exemplified in Beirut by an ancient family with Egyptian-Lebanese admixed members. But the genetic impact at a population level does not appear until the time of Alexander the Great (beginning 330 BCE), when a fusion of Asian and Near Easterner ancestry can be seen, paralleling the cultural fusion that appears in the archaeological records from this period. The Romans then conquered the region (31 BCE) but had little genetic impact over their 600 years of rule. Finally, during the Ottoman rule (beginning 1516 CE), Caucasus-related ancestry penetrated the Near East. Thus, in the past 4,000 years, three limited admixture events detectably impacted the population, complementing the historical records of this culturally complex region dominated by the elite with genetic insights from the general population.

INTRODUCTION: Large-scale human genome sequencing studies to date have been limited to large, metropolitan populations or to small numbers of genomes from each group. Much remains to be understood about the extent and structure of genetic variation in our species and how it was shaped by past population separations, admixture, adaptation, size changes, and gene flow from archaic human groups. Larger numbers of genome sequences from more diverse populations are needed to illuminate these questions. RATIONALE: We sequence 929 genomes from 54 geographically, linguistically and culturally diverse human populations to an average of 35x coverage, and analyze the variation among them. We also physically resolve the haplotype phase of 26 of these genomes using linked-read sequencing. RESULTS: We identify 67.3 million single-nucleotide polymorphisms (SNPs), 8.8 million small insertions or deletions (indels) and 40,736 copy number variants (CNVs). This includes hundreds of thousands of variants that had not been discovered by previous sequencing efforts but which are common in one or more population. We demonstrate benefits to the study of population relationships of genome sequences over ascertained array genotypes, particularly when involving African populations. Populations in central and southern Africa, the Americas and Oceania each harbour tens to hundreds of thousands of private, common genetic variants. The majority of these variants arose as novel mutations rather than through archaic introgression, except in Oceanian populations where many private variants derive from Denisovan admixture. While some reach high frequencies, no variants are fixed between major geographical regions. We estimate that the genetic separation between present-day human populations occurred mostly within the last 250,000 years. However, these early separations were gradual in nature and shaped by protracted gene flow. All populations thus still had some genetic contact more recently than this, but there is also evidence that a small fraction of present-day structure might be hundreds of thousands of years older. Most populations expanded in size over the last 10,000 years, but hunter-gatherer groups did not. The low diversity among the Neanderthal haplotypes segregating in present-day populations indicates that, while more than one Neanderthal individual must have contributed genetic material to modern humans, there was likely only one major episode of admixture. In contrast, Denisovan haplotype diversity reflects a more complex history involving more than one episode of admixture. We find small amounts of Neanderthal ancestry in West African genomes, most likely reflecting Eurasian admixture. Despite their very low levels or absence of archaic ancestry, African populations share many Neanderthal and Denisovan variants that are absent from Eurasia, reflecting how a larger proportion of the ancestral human variation has been maintained in Africa. CONCLUSION: The discovery of substantial amounts of common genetic variation that was previously undocumented, and is geographically restricted, highlights the continued value of anthropologically informed study designs for understanding human diversity. The genome sequences presented here are a freely available resource with relevance to population history, medical genetics, anthropology and linguistics. [Figure: see text]

Classic selective sweeps occur when positive selection increases a variant's frequency from low to high in a population, and underlie some long-studied human characteristics such as variation in skin, hair or eye colour. In such well-studied 'gold standard' examples, a known variant has been associated with a plausible phenotype and underlying selective force. Signatures of classic sweeps have more recently been detected in population-genetic data independently of any prior information about the corresponding phenotype or selective force, and usually without suggesting any insights into these. Motivated by the need to understand such candidates, we first review the gold standards and show that our understanding of them is often incomplete or unconvincing; only two of the examples we consider are compellingly explained. We assess approaches for large-scale association of classic sweep candidate variants to phenotypes and selective forces, test these on the gold standards, and discuss the standards of evidence needed to adequately understand a selective sweep.

PURPOSE The Affordable Care Act (ACA), enacted in 2010, created the Expansion of Physician Assistant Training (EPAT) grant with the goal of increasing the number of physician assistants (PAs) entering primary care. There has been no analysis regarding the practice patterns of students graduating from EPAT-funded programs. This study aimed to describe the workforce impact of federal investment in PA education through the EPAT program. METHODS In 2018 the authors administered an anonymous electronic survey to all 27 EPAT PA programs funded from 2010 to 2015. The goal was to assess program and graduate characteristics, practice patterns, and intention to apply to similar future opportunities. The survey was IRB exempt. RESULTS There was a 59.30% response rate representing 366 total graduates, which reflected 62.46% of the 586 Health Resources and Services Administration (HRSA)-reported total EPAT-funded students. Of the respondents, 16.41% of EPAT recipients self-identified as non-White, 4.54% indicated Hispanic ethnicity, 53.65% identified as being of disadvantaged status, and 32.92% reported coming from rural backgrounds. Sixty-three percent entered primary care immediately following graduation, while 87.88% reported practicing primary care immediately after graduation or at the last point of contact. Fifty-two percent of EPAT graduates practiced in medically underserved areas (MUAs). CONCLUSION Recipients of HRSA EPAT funding practiced in primary care specialties immediately following graduation at a rate that was 2.5 times higher than the national PA average. This specialty choice was durable for several years post-graduation. The EPAT program funded over 140 PA graduates who immediately practiced in MUAs. This funding supported a more racially and ethnically diverse student population and higher number of students coming from rural areas than the national average for PA students.

Objectives Thrombotic thrombocytopenic purpura (TTP) is a rare thrombotic microangiopathy (TMA) caused by ADAMTS13 deficiency with mortality of up to 90% in the absence of treatment, typically therapeutic plasma exchange (TPE). TTP presents similarly to other TMAs in which TPE is ineffective and associated with morbidity and additional costs. Thus, we sought to assess clinical and laboratory parameters differentiating TTP from other TMAs in our institution’s catchment population. Methods We reviewed 8 years of data from a Canadian provincial apheresis center, including 100 patients with suspected TMA who underwent ADAMTS13 testing, 35 of whom were diagnosed with TTP. We assessed clinical and laboratory parameters to identify discriminators of TTP and assigned PLASMIC TTP prediction scores. Results We observed a higher frequency of neurologic symptoms, more severe thrombocytopenia, and less creatinine elevation in TTP relative to other TMAs. High PLASMIC scores (6-7 points) had 83% sensitivity and 88% specificity for TTP diagnoses; however, ADAMTS13 activity testing was required for correct diagnoses in 14 cases. Conclusions Clinical and laboratory parameters including PLASMIC scoring may lead to misdiagnosis in some cases of TMA. ADAMST13 activity testing provides definitive diagnosis of TTP, supporting the role of rapid turnaround ADAMTS13 testing for appropriate treatment of TMAs.

Objectives: Despite substantial research linking adverse childhood experiences (ACEs) and health, it is unclear how associations differ by veteran status and military service era (draft, volunteer era). The current study evaluated differences in ACEs and health by veteran status and era, increasing understanding important for service provision as the volunteer era veteran population increases. Methods: Behavioral Risk Factor Surveillance System 2012 data were used in univariate and weighted multivariable logistic regression models to assess associations among veteran status, service era, ACEs, and health. Results: Volunteer era veterans experienced the most ACEs (M = 2.42); draft era veterans experienced the fewest (M = 1.04). Individuals reporting 3 or more ACEs were 3.67 times (95% CI = 3.22-4.19) more likely to endorse depression, 1.32 times (95% CI = 1.17-1.48) more likely to report poorer general health, and 1.77 times (95% CI = 1.58-1.97) more likely to endorse poorer physical health, compared to those reporting none. Volunteer era veterans were 2.43 times more likely to report poorer physical health (95% CI = 1.49-3.97) than draft era veterans, adjusting for ACEs. Conclusions: ACEs were associated with poorer health independent of veteran status and service era. Volunteer era veterans experienced more ACEs; need for trauma-informed services supporting whole health may increase.

Introduction The COVID-19 pandemic has caused widespread disruptions including to health services. In the early response to the pandemic many countries restricted population movements and some health services were suspended or limited. In late 2020 and early 2021 some countries re-imposed restrictions. Health authorities need to balance the potential harms of additional SARS-CoV-2 transmission due to contacts associated with health services against the benefits of those services, including fewer new HIV infections and deaths. This paper examines these trade-offs for select HIV services. Methods We used four HIV simulation models (Goals, HIV Synthesis, Optima HIV and EMOD) to estimate the benefits of continuing HIV services in terms of fewer new HIV infections and deaths. We used three COVID-19 transmission models (Covasim, Cooper/Smith and a simple contact model) to estimate the additional deaths due to SARS-CoV-2 transmission among health workers and clients. We examined four HIV services: voluntary medical male circumcision, HIV diagnostic testing, viral load testing and programs to prevent mother-to-child transmission. We compared COVID-19 deaths in 2020 and 2021 with HIV deaths occurring now and over the next 50 years discounted to present value. The models were applied to countries with a range of HIV and COVID-19 epidemics. Results Maintaining these HIV services could lead to additional COVID-19 deaths of 0.002 to 0.15 per 10,000 clients. HIV-related deaths averted are estimated to be much larger, 19–146 discounted deaths per 10,000 clients. Discussion While there is some additional short-term risk of SARS-CoV-2 transmission associated with providing HIV services, the risk of additional COVID-19 deaths is at least 100 times less than the HIV deaths averted by those services. Ministries of Health need to take into account many factors in deciding when and how to offer essential health services during the COVID-19 pandemic. This work shows that the benefits of continuing key HIV services are far larger than the risks of additional SARS-CoV-2 transmission.

Summary The Middle East region is important to understand human evolution and migrations but is underrepresented in genomic studies. Here, we generated 137 high-coverage physically phased genome sequences from eight Middle Eastern populations using linked-read sequencing. We found no genetic traces of early expansions out-of-Africa in present-day populations but found Arabians have elevated Basal Eurasian ancestry that dilutes their Neanderthal ancestry. Population sizes within the region started diverging 15–20 kya, when Levantines expanded while Arabians maintained smaller populations that derived ancestry from local hunter-gatherers. Arabians suffered a population bottleneck around the aridification of Arabia 6 kya, while Levantines had a distinct bottleneck overlapping the 4.2 kya aridification event. We found an association between movement and admixture of populations in the region and the spread of Semitic languages. Finally, we identify variants that show evidence of selection, including polygenic selection. Our results provide detailed insights into the genomic and selective histories of the Middle East., Graphical abstract, Highlights • Middle Easterners do not have ancestry from an early out-of-Africa expansion • Basal Eurasian and African ancestry in Arabians deplete their Neanderthal ancestry • Populations experienced bottlenecks overlapping aridification events • Identification of recent single and polygenic signals of selection in Arabia, A high-coverage resource of physically phased genomes from eight Middle Eastern populations generated via linked-read sequencing provides insights into a genetically understudied region and enables more comprehensive study of population history and the detection of millions of variants common to the Middle East but outside short-read accessibility masks and not previously cataloged. It enhances our understanding of regional ancestry, the spread of languages, the effects of climate change on populations, and the evolutionary history of genetic variants.

The genomes of present-day humans outside Africa originated almost entirely from a single migration out ~50,000-70,000 years ago[1, 2], followed by mixture with Neanderthals contributing ~2% to all non-Africans [3, 4]. However, the details of this initial migration remain poorly-understood because no ancient DNA analyses are available from this key time period, and interpretation of present-day autosomal data is complicated due to subsequent population movements/reshaping [5]. One locus, however, does retain male-specific information from this early period: the Y-chromosome, where a detailed calibrated phylogeny has been constructed [6]. Three present-day Y lineages were carried by the initial migration: the rare haplogroup D, the moderately rare C, and the very common FT lineage which now dominates most non-African populations [6, 7]. We show that phylogenetic analyses of haplogroup C, D and FT sequences, including very rare deep-rooting lineages, together with phylogeographic analyses of ancient and present-day non-African Y-chromosomes, all point to East/South-east Asia as the origin 50,000-55,000 years ago of all known non-African male lineages (apart from recent migrants). This observation contrasts with the expectation of a West Eurasian origin predicted by a simple model of expansion from a source near Africa [8, 9], and can be interpreted as resulting from extensive genetic drift in the initial population or replacement of early western lineages from the east, thus informing and constraining models of the initial expansion.

The genomes of humans outside Africa originated almost entirely from a single migration out ∼50,000-60,000 years ago1,2, followed closely by mixture with Neanderthals contributing ∼2% to all non-Africans3,4. However, the details of this initial migration remain poorly-understood because no ancient DNA analyses are available from this key time period, and present-day autosomal data are uninformative due to subsequent population movements/reshaping5. One locus, however, does retain extensive information from this early period: the Y-chromosome, where a detailed calibrated phylogeny has been constructed6. Three present-day Y lineages were carried by the initial migration: the rare haplogroup D, the moderately rare C, and the very common FT lineage which now dominates most non-African populations6,7. We show that phylogenetic analyses of haplogroup C, D and FT sequences, including very rare deep-rooting lineages, together with phylogeographic analyses of ancient and present-day non-African Y-chromosomes, all point to East/South-east Asia as the origin 50,000-55,000 years ago of all known non-African male lineages (apart from recent migrants). This implies that the initial Y lineages in populations between Africa and eastern Asia have been entirely replaced by lineages from the east, contrasting with the expectations of the serial-founder model8,9, and thus informing and constraining models of the initial expansion.

Genomic studies in African populations provide unique opportunities to understand disease etiology, human diversity, and population history. In the largest study of its kind, comprising genome-wide data from 6,400 individuals and whole-genome sequences from 1,978 individuals from rural Uganda, we find evidence of geographically correlated fine-scale population substructure. Historically, the ancestry of modern Ugandans was best represented by a mixture of ancient East African pastoralists. We demonstrate the value of the largest sequence panel from Africa to date as an imputation resource. Examining 34 cardiometabolic traits, we show systematic differences in trait heritability between European and African populations, probably reflecting the differential impact of genes and environment. In a multi-trait pan-African GWAS of up to 14,126 individuals, we identify novel loci associated with anthropometric, hematological, lipid, and glycemic traits. We find that several functionally important signals are driven by Africa-specific variants, highlighting the value of studying diverse populations across the region.

We report high-coverage whole-genome sequencing data from 46 Yemeni individuals as well as genome-wide genotyping data from 169 Yemenis from diverse locations. We use this dataset to define the genetic diversity in Yemen and how it relates to people elsewhere in the Near East. Yemen is a vast region with substantial cultural and geographic diversity, but we found little genetic structure correlating with geography among the Yemenis – probably reflecting continuous movement of people between the regions. African ancestry from admixture in the past 800 years is widespread in Yemen and is the main contributor to the country’s limited genetic structure, with some individuals in Hudayda and Hadramout having up to 20% of their genetic ancestry from Africa. In contrast, individuals from Maarib appear to have been genetically isolated from the African gene flow and thus have genomes likely to reflect Yemen’s ancestry before the admixture. This ancestry was comparable to the ancestry present during the Bronze Age in the distant Northern regions of the Near East. After the Bronze Age, the South and North of the Near East therefore followed different genetic trajectories: in the North the Levantines admixed with a Eurasian population carrying steppe ancestry whose impact never reached as far south as the Yemen, where people instead admixed with Africans leading to the genetic structure observed in the Near East today.

Understanding human genetic diversity in Africa is important for interpreting the evolution of all humans, yet vast regions in Africa, such as Chad, remain genetically poorly investigated. Here, we use genotype data from 480 samples from Chad, the Near East, and southern Europe, as well as whole-genome sequencing from 19 of them, to show that many populations today derive their genomes from ancient African-Eurasian admixtures. We found evidence of early Eurasian backflow to Africa in people speaking the unclassified isolate Laal language in southern Chad and estimate from linkage-disequilibrium decay that this occurred 4,750–7,200 years ago. It brought to Africa a Y chromosome lineage (R1b-V88) whose closest relatives are widespread in present-day Eurasia; we estimate from sequence data that the Chad R1b-V88 Y chromosomes coalesced 5,700–7,300 years ago. This migration could thus have originated among Near Eastern farmers during the African Humid Period. We also found that the previously documented Eurasian backflow into Africa, which occurred ∼3,000 years ago and was thought to be mostly limited to East Africa, had a more westward impact affecting populations in northern Chad, such as the Toubou, who have 20%–30% Eurasian ancestry today. We observed a decline in heterozygosity in admixed Africans and found that the Eurasian admixture can bias inferences on their coalescent history and confound genetic signals from adaptation and archaic introgression.

Manuel, Marc de et al., Our closest living relatives, chimpanzees and bonobos, have a complex demographic history. We analyzed the high-coverage whole genomes of 75 wild-born chimpanzees and bonobos from 10 countries in Africa. We found that chimpanzee population substructure makes genetic information a good predictor of geographic origin at country and regional scales. Multiple lines of evidence suggest that gene flow occurred from bonobos into the ancestors of central and eastern chimpanzees between 200,000 and 550,000 years ago, probably with subsequent spread into Nigeria-Cameroon chimpanzees. Together with another, possibly more recent contact (after 200,000 years ago), bonobos contributed less than 1% to the central chimpanzee genomes. Admixture thus appears to have been widespread during hominid evolution., M.d.M. is supported by a Formació de personal Investigador fellowship from Generalitat de Catalunya (FI_B01111). M.K. is supported by a Deutsche Forschungsgemeinschaft fellowship (KU 3467/1-1). V.C.S., I.D., and L.E. are supported by Swiss National Science Foundation grants 31003A-143393 and 310030B-16660. T.D. is funded by the Gates Cambridge Trust. O.L. is supported by a Ramón y Cajal grant from Ministerio de Economía y Competitividad (MINECO) (RYC-2013-14797) and MINECO grant BFU2015-68759-P [Fondo Europeo de Desarrollo Region (FEDER)]. P.H. is supported by Estonian Research Council grant PUT1036. J.M.S., A.M.A., and S.C. are funded by the Max Planck Society. J.P.-M., C.T.-S., and Y.X. were supported by The Wellcome Trust (098051). J.M.H.-G. is supported by the María de Maeztu Programme (MDM-2014-0370). A.S. is supported by an Isaac Newton Trust/Wellcome Trust Institutional Strategic Support Fund Joint Research Grant. J.N. had support from a U.S. NIH U01CA198933 grant, and B.M.P. is supported by a Swiss National Science Foundation postdoctoral fellowship. A.N. is supported by MINECO grant BFU2015-68649-P. The collection of fecal samples was supported by the Max Planck Society and Krekeler Foundation’s generous funding for the Pan African Programme. T.M.-B. thanks ICREA; the European Molecular Biology Organization Young Investigator Programme 2013; MINECO grants BFU2014-55090-P (FEDER), BFU2015-7116-ERC, and BFU2015-6215-ERCU01; U.S. NIH grant MH106874; Fundacio Zoo Barcelona; and Secretaria d’Universitats i Recerca del Departament d’Economia i Coneixement de la Generalitat de Catalunya for the support to his laboratory.

Rare gene knockouts in adult humans On average, most people's genomes contain approximately 100 completely nonfunctional genes. These loss-of-function (LOF) mutations tend to be rare and/or occur only as a single copy within individuals. Narasimhan et al. investigated LOF in a Pakistani population with high levels of consanguinity. Examining LOF alleles that were identical by descent, they found, as expected, an absence of homozygote LOF for certain protein-coding genes. However, they also identified many homozygote LOF alleles with no apparent deleterious phenotype, including some that were expected to confer genetic disease. Indeed, one family had lost the recombination-associated gene PRDM9 . Science , this issue p. 474

BackgroundThe Parsis, one of the smallest religious community in the world, reside in South Asia. Previous genetic studies on them, although based on low resolution markers, reported both Iranian and Indian ancestries. To understand the population structure and demographic history of this group in more detail, we analyzed Indian and Pakistani Parsi populations using high-resolution autosomal and uniparental (Y-chromosomal and mitochondrial DNA) markers. Additionally, we also assayed 108 mitochondrial DNA markers among 21 ancient Parsi DNA samples excavated from Sanjan, in present day Gujarat, the place of their original settlement in India.ResultsOur extensive analyses indicated that among present-day populations, the Parsis are genetically closest to Middle Eastern (Iranian and the Caucasus) populations rather than their South Asian neighbors. They also share the highest number of haplotypes with present-day Iranians and we estimate that the admixture of the Parsis with Indian populations occurred ∼1,200 years ago. Enriched homozygosity in the Parsi reflects their recent isolation and inbreeding. We also observed 48% South-Asian-specific mitochondrial lineages among the ancient samples, which might have resulted from the assimilation of local females during the initial settlement.ConclusionsWe show that the Parsis are genetically closest to the Neolithic Iranians, followed by present-day Middle Eastern populations rather than those in South Asia and provide evidence of sex-specific admixture from South Asians to the Parsis. Our results are consistent with the historically-recorded migration of the Parsi populations to South Asia in the 7thcentury and in agreement with their assimilation into the Indian sub-continent’s population and cultural milieu “like sugar in milk”. Moreover, in a wider context our results suggest a major demographic transition in West Asia due to Islamic-conquest.

Multiple questions relating to contributions of cultural and demographical factors in the process of human geographical dispersal remain largely unanswered. India, a land of early human settlement and the resulting diversity is a good place to look for some of the answers. In this study, we explored the genetic structure of India using a diverse panel of 78 males genotyped using the GenoChip. Their genome-wide single-nucleotide polymorphism (SNP) diversity was examined in the context of various covariates that influence Indian gene pool. Admixture analysis of genome-wide SNP data showed high proportion of the Southwest Asian component in all of the Indian samples. Hierarchical clustering based on admixture proportions revealed seven distinct clusters correlating to geographical and linguistic affiliations. Convex hull overlay of Y-chromosomal haplogroups on the genome-wide SNP principal component analysis brought out distinct non-overlapping polygons of F*-M89, H*-M69, L1-M27, O2a-M95 and O3a3c1-M117, suggesting a male-mediated migration and expansion of the Indian gene pool. Lack of similar correlation with mitochondrial DNA clades indicated a shared genetic ancestry of females. We suggest that ancient male-mediated migratory events and settlement in various regional niches led to the present day scenario and peopling of India.

We have assessed copy number variation (CNV) in the male-specific part of the human Y chromosome discovered by array comparative genomic hybridization (array-CGH) in 411 apparently healthy UK males, and validated the findings using SNP genotype intensity data available for 149 of them. After manual curation taking account of the complex duplicated structure of Y-chromosomal sequences, we discovered 22 curated CNV events considered validated or likely, mean 0.93 (range 0–4) per individual. 16 of these were novel. Curated CNV events ranged in size from 3 Mb, and in frequency from 1/411 to 107/411. Of the 24 protein-coding genes or gene families tested, nine showed CNV. These included a large duplication encompassing the AMELY and TBL1Y genes that probably has no phenotypic effect, partial deletions of the TSPY cluster and AZFc region that may influence spermatogenesis, and other variants with unknown functional implications, including abundant variation in the number of RBMY genes and/or pseudogenes, and a novel complex duplication of two segments overlapping the AZFa region and including the 3′ end of the UTY gene. Erratum (https://dx.doi.org/10.1007%2Fs00439-015-1565-2): The second author’s initial was missing, and the fifth to eighth authors’ initials were incorrect. The correct names are Tomas W. Fitzgerald, Blair H. Smith, Anna F. Dominiczak, Andrew D. Morris, and David J. Porteous. The complete author list is given below: Wei Wei, Tomas W. Fitzgerald, Qasim Ayub, Andrea Massaia, Blair H. Smith, Anna F. Dominiczak, Andrew D. Morris, David J. Porteous, Matthew E. Hurles, Chris Tyler-Smith, Yali Xue

The Y-chromosomal genetic landscape of South America is relatively homogenous. The majority of native Amerindian people are assigned to haplogroup Q and only a small percentage belongs to haplogroup C. With the aim of further differentiating the major Q lineages and thus obtaining new insights into the population history of South America, two individuals, both belonging to the sub-haplogroup Q-M3, were analyzed with next-generation sequencing. Several new candidate SNPs were evaluated and four were confirmed to be new, haplogroup Q-specific, and variable. One of the new SNPs, named MG2, identifies a new sub-haplogroup downstream of Q-M3; the other three (MG11, MG13, MG15) are upstream of Q-M3 but downstream of M242, and describe branches at the same phylogenetic positions as previously known SNPs in the samples tested. These four SNPs were typed in 100 individuals belonging to haplogroup Q.

Archaeological, palaeontological and geological evidence shows that post-glacial warming released human populations from their various climate-bound refugia. Yet specific connections between these refugia and the timing and routes of post-glacial migrations that ultimately established modern patterns of genetic variation remain elusive. Here, we use Y-chromosome markers combined with autosomal data to reconstruct population expansions from regional refugia in Southwest Asia. Populations from three regions in particular possess distinctive autosomal genetic signatures indicative of likely refugia: one, in the north, centered around the eastern coast of the Black Sea, the second, with a more Levantine focus, and the third in the southern Arabian Peninsula. Modern populations from these three regions carry the widest diversity and may indeed represent the most likely descendants of the populations responsible for the Neolithic cultures of Southwest Asia. We reveal the distinct and datable expansion routes of populations from these three refugia throughout Southwest Asia and into Europe and North Africa and discuss the possible correlations of these migrations to various cultural and climatic events evident in the archaeological record of the past 15,000 years.

We present a new method, Fine-Mapping of Adaptive Variation (FineMAV), which combines population differentiation, derived allele frequency, and molecular functionality to prioritize positively selected candidate variants for functional follow-up. We calibrate and test FineMAV using eight experimentally validated “gold standard” positively selected variants and simulations. FineMAV has good sensitivity and a low false discovery rate. Applying FineMAV to the 1000 Genomes Project Phase 3 SNP dataset, we report many novel selected variants, including ones in TGM3 and PRSS53 associated with hair phenotypes that we validate using available independent data. FineMAV is widely applicable to sequence data from both human and other species. Electronic supplementary material The online version of this article (10.1186/s13059-017-1380-2) contains supplementary material, which is available to authorized users.

We describe the variation in copy number of a ~ 10 kb region overlapping the long intergenic noncoding RNA (lincRNA) gene, TTTY22, within the IR3 inverted repeat on the short arm of the human Y chromosome, leading to individuals with 0–3 copies of this region in the general population. Variation of this CNV is common, with 266 individuals having 0 copies, 943 (including the reference sequence) having 1, 23 having 2 copies, and two having 3 copies, and was validated by breakpoint PCR, fibre-FISH, and 10× Genomics Chromium linked-read sequencing in subsets of 1234 individuals from the 1000 Genomes Project. Mapping the changes in copy number to the phylogeny of these Y chromosomes previously established by the Project identified at least 20 mutational events, and investigation of flanking paralogous sequence variants showed that the mutations involved flanking sequences in 18 of these, and could extend over > 30 kb of DNA. While either gene conversion or double crossover between misaligned sister chromatids could formally explain the 0–2 copy events, gene conversion is the more likely mechanism, and these events include the longest non-allelic gene conversion reported thus far. Chromosomes with three copies of this CNV have arisen just once in our data set via another mechanism: duplication of 420 kb that places the third copy 230 kb proximal to the existing proximal copy. Our results establish gene conversion as a previously under-appreciated mechanism of generating copy number changes in humans and reveal the exceptionally large size of the conversion events that can occur.

The Canaanites inhabited the Levant region during the Bronze Age and established a culture which became influential in the Near East and beyond. However, the Canaanites, unlike most other ancient Near Easterners of this period, left few surviving textual records and thus their origin and relationship to ancient and present-day populations remain unclear. In this study, we sequenced five whole-genomes from ~3,700-year-old individuals from the city of Sidon, a major Canaanite city-state on the Eastern Mediterranean coast. We also sequenced the genomes of 99 individuals from present-day Lebanon to catalogue modern Levantine genetic diversity. We find that a Bronze Age Canaanite-related ancestry was widespread in the region, shared among urban populations inhabiting the coast (Sidon) and inland populations (Jordan) who likely lived in farming societies or were pastoral nomads. This Canaanite-related ancestry derived from mixture between local Neolithic populations and eastern migrants genetically related to Chalcolithic Iranians. We estimate, using linkage-disequilibrium decay patterns, that admixture occurred 6,600-3,550 years ago, coinciding with massive population movements in the mid-Holocene triggered by aridification ~4,200 years ago. We show that present-day Lebanese derive most of their ancestry from a Canaanite-related population, which therefore implies substantial genetic continuity in the Levant since at least the Bronze Age. In addition, we find Eurasian ancestry in the Lebanese not present in Bronze Age or earlier Levantines. We estimate this Eurasian ancestry arrived in the Levant around 3,750-2,170 years ago during a period of successive conquests by distant populations such as the Persians and Macedonians.

Heterozygous mutations within homozygous sequences descended from a recent common ancestor offer a way to ascertain de novo mutations across multiple generations. Using exome sequences from 3222 British-Pakistani individuals with high parental relatedness, we estimate a mutation rate of 1.45 ± 0.05 × 10−8 per base pair per generation in autosomal coding sequence, with a corresponding non-crossover gene conversion rate of 8.75 ± 0.05 × 10−6 per base pair per generation. This is at the lower end of exome mutation rates previously estimated in parent–offspring trios, suggesting that post-zygotic mutations contribute little to the human germ-line mutation rate. We find frequent recurrence of mutations at polymorphic CpG sites, and an increase in C to T mutations in a 5ʹ CCG 3ʹ to 5ʹ CTG 3ʹ context in the Pakistani population compared to Europeans, suggesting that mutational processes have evolved rapidly between human populations., Estimates of human mutation rates differ substantially based on the approach. Here, the authors present a multi-generational estimate from the autozygous segment in a non-European population that gives insight into the contribution of post-zygotic mutations and population-specific mutational processes.

The properties of the human Y chromosome - namely, male specificity, haploidy and escape from crossing over - make it an unusual component of the genome, and have led to its genetic variation becoming a key part of studies of human evolution, population history, genealogy, forensics and male medical genetics. Next-generation sequencing (NGS) technologies have driven recent progress in these areas. In particular, NGS has yielded direct estimates of mutation rates, and an unbiased and calibrated molecular phylogeny that has unprecedented detail. Moreover, the availability of direct-to-consumer NGS services is fuelling a rise of 'citizen scientists', whose interest in resequencing their own Y chromosomes is generating a wealth of new data.

Aboriginal Australians represent one of the oldest continuous cultures outside Africa, with evidence indicating that their ancestors arrived in the ancient landmass of Sahul (present-day New Guinea and Australia) ~55 thousand years ago. Genetic studies, though limited, have demonstrated both the uniqueness and antiquity of Aboriginal Australian genomes. We have further resolved known Aboriginal Australian mitochondrial haplogroups and discovered novel indigenous lineages by sequencing the mitogenomes of 127 contemporary Aboriginal Australians. In particular, the more common haplogroups observed in our dataset included M42a, M42c, S, P5 and P12, followed by rarer haplogroups M15, M16, N13, O, P3, P6 and P8. We propose some major phylogenetic rearrangements, such as in haplogroup P where we delinked P4a and P4b and redefined them as P4 (New Guinean) and P11 (Australian), respectively. Haplogroup P2b was identified as a novel clade potentially restricted to Torres Strait Islanders. Nearly all Aboriginal Australian mitochondrial haplogroups detected appear to be ancient, with no evidence of later introgression during the Holocene. Our findings greatly increase knowledge about the geographic distribution and phylogenetic structure of mitochondrial lineages that have survived in contemporary descendants of Australia’s first settlers.

The Armenians are a culturally isolated population who historically inhabited a region in the Near East bounded by the Mediterranean and Black seas and the Caucasus, but remain under-represented in genetic studies and have a complex history including a major geographic displacement during World War I. Here, we analyse genome-wide variation in 173 Armenians and compare them with 78 other worldwide populations. We find that Armenians form a distinctive cluster linking the Near East, Europe, and the Caucasus. We show that Armenian diversity can be explained by several mixtures of Eurasian populations that occurred between ~3000 and ~2000 bce, a period characterized by major population migrations after the domestication of the horse, appearance of chariots, and the rise of advanced civilizations in the Near East. However, genetic signals of population mixture cease after ~1200 bce when Bronze Age civilizations in the Eastern Mediterranean world suddenly and violently collapsed. Armenians have since remained isolated and genetic structure within the population developed ~500 years ago when Armenia was divided between the Ottomans and the Safavid Empire in Iran. Finally, we show that Armenians have higher genetic affinity to Neolithic Europeans than other present-day Near Easterners, and that 29% of Armenian ancestry may originate from an ancestral population that is best represented by Neolithic Europeans., This work was supported by Wellcome Trust grant 098051.

The predominantly African origin of all modern human populations is well established, but the route taken out of Africa is still unclear. Two alternative routes, via Egypt and Sinai or across the Bab el Mandeb strait into Arabia, have traditionally been proposed as feasible gateways in light of geographic, paleoclimatic, archaeological, and genetic evidence. Distinguishing among these alternatives has been difficult. We generated 225 whole-genome sequences (225 at 8× depth, of which 8 were increased to 30×; Illumina HiSeq 2000) from six modern Northeast African populations (100 Egyptians and five Ethiopian populations each represented by 25 individuals). West Eurasian components were masked out, and the remaining African haplotypes were compared with a panel of sub-Saharan African and non-African genomes. We showed that masked Northeast African haplotypes overall were more similar to non-African haplotypes and more frequently present outside Africa than were any sets of haplotypes derived from a West African population. Furthermore, the masked Egyptian haplotypes showed these properties more markedly than the masked Ethiopian haplotypes, pointing to Egypt as the more likely gateway in the exodus to the rest of the world. Using five Ethiopian and three Egyptian high-coverage masked genomes and the multiple sequentially Markovian coalescent (MSMC) approach, we estimated the genetic split times of Egyptians and Ethiopians from non-African populations at 55,000 and 65,000 years ago, respectively, whereas that of West Africans was estimated to be 75,000 years ago. Both the haplotype and MSMC analyses thus suggest a predominant northern route out of Africa via Egypt.

Vitamin D and folate are activated and degraded by sunlight, respectively, and the physiological processes they control are likely to have been targets of selection as humans expanded from Africa into Eurasia. We investigated signals of positive selection in gene sets involved in the metabolism, regulation and action of these two vitamins in worldwide populations sequenced by Phase I of the 1000 Genomes Project. Comparing allele frequency-spectrum-based summary statistics between these gene sets and matched control genes, we observed a selection signal specific to East Asians for a gene set associated with vitamin D action in bones. The selection signal was mainly driven by three genes CXXC finger protein 1 (CXXC1), low density lipoprotein receptor-related protein 5 (LRP5) and runt-related transcription factor 2 (RUNX2). Examination of population differentiation and haplotypes allowed us to identify several candidate causal regulatory variants in each gene. Four of these candidate variants (one each in CXXC1 and RUNX2 and two in LRP5) had a >70% derived allele frequency in East Asians, but were present at lower (20–60%) frequency in Europeans as well, suggesting that the adaptation might have been part of a common response to climatic and dietary changes as humans expanded out of Africa, with implications for their role in vitamin D-dependent bone mineralization and osteoporosis insurgence. We also observed haplotype sharing between East Asians, Finns and an extinct archaic human (Denisovan) sample at the CXXC1 locus, which is best explained by incomplete lineage sorting., This work was supported by The Wellcome Trust (098051). EA was supported by the Erasmus Lifelong Learning Programme (LLP). LP was supported by the ERC Starting Investigator grant FP7 – 261213.

We present 42 new Y-chromosomal sequences from diverse Indian tribal and non-tribal populations, including the Jarawa and Onge from the Andaman Islands, which are analysed within a calibrated Y-chromosomal phylogeny incorporating South Asian (in total 305 individuals) and worldwide (in total 1286 individuals) data from the 1000 Genomes Project. In contrast to the more ancient ancestry in the South than in the North that has been claimed, we detected very similar coalescence times within Northern and Southern non-tribal Indian populations. A closest neighbour analysis in the phylogeny showed that Indian populations have an affinity towards Southern European populations and that the time of divergence from these populations substantially predated the Indo-European migration into India, probably reflecting ancient shared ancestry rather than the Indo-European migration, which had little effect on Indian male lineages. Among the tribal populations, the Birhor (Austro-Asiatic-speaking) and Irula (Dravidian-speaking) are the nearest neighbours of South Asian non-tribal populations, with a common origin in the last few millennia. In contrast, the Riang (Tibeto-Burman-speaking) and Andamanese have their nearest neighbour lineages in East Asia. The Jarawa and Onge shared haplogroup D lineages with each other within the last ~7000 years, but had diverged from Japanese haplogroup D Y-chromosomes ~53000 years ago, most likely by a split from a shared ancestral population. This analysis suggests that Indian populations have complex ancestry which cannot be explained by a single expansion model. Funding was provided by the joint Spain–India bilateral grant PRI-PIBIN-2011-0942 and BFU2016-77961-P (AEI/ FEDER, UE) both awarded by the Ministerio de Economía y Competitividad (Spain) and with the support of Secretaria d’Universitats i Recerca del Departament d’Economia i Coneixement de la Generalitat de Catalunya (GRC 2014 SGR 866). Anders Bergström, YaliXue and Chris Tyler-Smith were supported by The Wellcome Trust (Grant 098051)

International audience; From the eighth century onward, the Indian Ocean was the scene of extensive trade of sub-Saharan African slaves via sea routes controlled by Muslim Arab and Swahili traders. Several populations in present-day Pakistan and India are thought to be the descendants of such slaves, yet their history of admixture and natural selection remains largely undefined. Here, we studied the genome-wide diversity of the African-descent Makranis, who reside on the Arabian Sea coast of Pakistan, as well that of four neighboring Pakistani populations , to investigate the genetic legacy, population dynamics, and tempo of the Indian Ocean slave trade. We show that the Makranis are the result of an admixture event between local Baluch tribes and Bantu-speaking populations from eastern or southeastern Africa; we dated this event to $300 years ago during the Omani Empire domination. Levels of parental relatedness, measured through runs of ho-mozygosity, were found to be similar across Pakistani populations, suggesting that the Makranis rapidly adopted the traditional practice of endogamous marriages. Finally, we searched for signatures of post-admixture selection at traits evolving under positive selection, including skin color, lactase persistence, and resistance to malaria. We demonstrate that the African-specific Duffy-null blood group-believed to confer resistance against Plasmodium vivax infection-was recently introduced to Pakistan through the slave trade and evolved adaptively in this P. vivax malaria-endemic region. Our study reconstructs the genetic and adaptive history of a neglected episode of the African Diaspora and illustrates the impact of recent admixture on the diffusion of adaptive traits across human populations.

Here we report the Simons Genome Diversity Project data set: high quality genomes from 300 individuals from 142 diverse populations. These genomes include at least 5.8 million base pairs that are not present in the human reference genome. Our analysis reveals key features of the landscape of human genome variation, including that the rate of accumulation of mutations has accelerated by about 5% in non-Africans compared to Africans since divergence. We show that the ancestors of some pairs of present-day human populations were substantially separated by 100,000 years ago, well before the archaeologically attested onset of behavioural modernity. We also demonstrate that indigenous Australians, New Guineans and Andamanese do not derive substantial ancestry from an early dispersal of modern humans; instead, their modern human ancestry is consistent with coming from the same source as that of other non-Africans., Facultad de Ciencias Naturales y Museo

High-coverage whole-genome sequence studies have so far focused on a limited number1 of geographically restricted populations2, 3, 4, 5, or been targeted at specific diseases, such as cancer6. Nevertheless, the availability of high- resolution genomic data has led to the development of new methodologies for inferring population history7, 8, 9 and refuelled the debate on the mutation rate in humans10. Here we present the Estonian Biocentre Human Genome Diversity Panel (EGDP), a dataset of 483 high-coverage human genomes from 148 populations worldwide, including 379 new genomes from 125 populations, which we group into diversity and selection sets. We analyse this dataset to refine estimates of continent-wide patterns of heterozygosity, long- and short-distance gene flow, archaic admixture, and changes in effective population size through time as well as for signals of positive or balancing selection. We find a genetic signature in present-day Papuans that suggests that at least 2% of their genome originates from an early and largely extinct expansion of anatomically modern humans (AMHs) out of Africa. Together with evidence from the western Asian fossil record11, and admixture between AMHs and Neanderthals predating the main Eurasian expansion12, our results contribute to the mounting evidence for the presence of AMHs out of Africa earlier than 75, 000 years ago.

We have analyzed Y-chromosomal variation in populations from Transoxiana, a historical region covering the southwestern part of Central Asia. We studied 780 samples from 10 regional populations of Kazakhs, Uzbeks, Turkmens, Dungans, and Karakalpaks using 35 SNP and 17 STR markers. Analysis of haplogroup frequencies using multidimensional scaling and principal component plots, supported by an analysis of molecular variance, showed that the geographic landscape of Transoxiana, despite its distinctiveness and diversity (deserts, fertile river basins, foothills and plains) had no strong influence on the genetic landscape. The main factor structuring the gene pool was the mode of subsistence: settled agriculture or nomadic pastoralism. Investigation of STR-based clusters of haplotypes and their ages revealed that cultural and demic expansions of Transoxiana were not closely connected with each other. The Arab cultural expansion introduced Islam to the region but did not leave a significant mark on the pool of paternal lineages. The Mongol expansion, in contrast, had enormous demic success, but did not impact cultural elements like language and religion. The genealogy of Muslim missionaries within the settled agricultural communities of Transoxiana was based on spiritual succession passed from teacher to disciple. However, among Transoxianan nomads, spiritual and biological succession became merged.

Scally, A. et al., Gorillas are humans' closest living relatives after chimpanzees, and are of comparable importance for the study of human origins and evolution. Here we present the assembly and analysis of a genome sequence for the western lowland gorilla, and compare the whole genomes of all extant great ape genera. We propose a synthesis of genetic and fossil evidence consistent with placing the human-chimpanzee and human-chimpanzee-gorilla speciation events at approximately 6 and 10 million years ago. In 30% of the genome, gorilla is closer to human or chimpanzee than the latter are to each other; this is rarer around coding genes, indicating pervasive selection throughout great ape evolution, and has functional consequences in gene expression. A comparison of protein coding genes reveals approximately 500 genes showing accelerated evolution on each of the gorilla, human and chimpanzee lineages, and evidence for parallel acceleration, particularly of genes involved in hearing. We also compare the western and eastern gorilla species, estimating an average sequence divergence time 1.75 million years ago, but with evidence for more recent genetic exchange and a population bottleneck in the eastern species. The use of the genome sequence in these and future analyses will promote a deeper understanding of great ape biology and evolution. © 2012 Macmillan Publishers Limited. All rights reserved., This research was supported in part by Wellcome Trust grants WT062023(toJ.H.,K.B.,S.F.,A.J.V.,P.F.),WT089066(toR.D.),WT077192(toR.D.,S.M., A.K.-K., J.T.S., W.W.), WT077009 (to Y.X., B.Y., Q.A., Y.C., C.T.-S.), WT077198 (to G.K.L.) and 075491/Z/04 (to G.L.); EMBL grants (to P.C.S., P.F.); scholarships from the Gates Cambridge Trust (to G.E.J. and T.D.O’C.); an MRC Special Fellowship in Biomedical Informatics (toA.S.);funding from the Lundbeck Foundation(toA.H.);the Academy of Finland and the Emil Aaltonen Foundation(toT.L.);a Marie Curie fellowship(toT.M.-B.); the European Community’s Seventh Framework Programme (FP7/2007-2013)/ ERC Starting Grant(StG_20091118)(toT.M.-B.);an FPI grant from the Spanish Ministry of Education (BES-2010-032251) (to J.P.-M.); a BBSRC Doctoral Training Grant (to S.H.M.); grants from the UK Medical Research Council (to A.H., S.M., C.P.P.); the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health(to J.C.M.);the Danish Council for Independent Research, Natural Sciences,grant no.09-062535(toK.M.,M.H.S.);a Commonwealth Scholarship (to M.C.W.); the Swiss National Science Foundation, Louis Jeantet Foundation (to E.T.D.); an ERC Starting Grant and an EMBO Young Investigator Award, Hutchinson Whampoa (to D.T.O.); NHGRI support (to W.C.W.); support from BIOBASE GmbH (to E.V.B., P.D.S., M.M., A.D.P., K.S., D.N.C.); US National Science Foundation grant DGE-0739133(toW.W.);NHGRIU54HG003079(toR.K.W.);NIHgrantHG002385(to E.E.E). E.E.E. is an investigator of the Howard Hughes Medical Institute.

Isolated populations can empower the identification of rare variation associated with complex traits through next generation association studies, but the generalizability of such findings remains unknown. Here we genotype 1,267 individuals from a Greek population isolate on the Illumina HumanExome Beadchip, in search of functional coding variants associated with lipids traits. We find genome-wide significant evidence for association between R19X, a functional variant in APOC3, with increased high-density lipoprotein and decreased triglycerides levels. Approximately 3.8% of individuals are heterozygous for this cardioprotective variant, which was previously thought to be private to the Amish founder population. R19X is rare (, Isolated populations may empower genetic association studies of complex traits. Here, the authors identify a rare cardioprotective APOC3 variant in a Greek population isolate and highlight the value of using population isolates to detect rare variants that confer disease risk.

Y-chromosomal variation in West Asian populations has so far been studied in less detail than in the neighboring Europe. Here, we analyzed 598 Y-chromosomes from two West Asian subregions-Transcaucasia and the Armenian plateau-using 40 Y-SNPs and 17 Y-STRs and combined them with previously published data from the region. The West Asian populations fell into two clusters: upland populations from the Anatolian, Armenian and Iranian plateaus, and lowland populations from the Levant, Mesopotamia and the Arabian Peninsula. This geographic subdivision corresponds with the linguistic difference between Indo-European and Turkic speakers, on the one hand, and Semitic speakers, on the other. This subdivision could be traced back to the Neolithic epoch, when upland populations from the Anatolian and Iranian plateaus carried similar haplogroup spectra but did not overlap with lowland populations from the Levant. We also found that the initial gene pool of the Armenian motherland population has been well preserved in most groups of the Armenian Diaspora. In view of the contribution of West Asians to the autosomal gene pool of the steppe Yamnaya archaeological culture, we sequenced a large portion of the Y-chromosome in haplogroup R1b samples from present-day East European steppe populations. The ancient Yamnaya samples are located on the "eastern" R-GG400 branch of haplogroup R1b-L23, showing that the paternal descendants of the Yamnaya still live in the Pontic steppe and that the ancient Yamnaya population was not an important source of paternal lineages in present-day West Europeans.

We have assessed the numbers of potentially deleterious variants in the genomes of apparently healthy humans by using (1) low-coverage whole-genome sequence data from 179 individuals in the 1000 Genomes Pilot Project and (2) current predictions and databases of deleterious variants. Each individual carried 281–515 missense substitutions, 40–85 of which were homozygous, predicted to be highly damaging. They also carried 40–110 variants classified by the Human Gene Mutation Database (HGMD) as disease-causing mutations (DMs), 3–24 variants in the homozygous state, and many polymorphisms putatively associated with disease. Whereas many of these DMs are likely to represent disease-allele-annotation errors, between 0 and 8 DMs (0–1 homozygous) per individual are predicted to be highly damaging, and some of them provide information of medical relevance. These analyses emphasize the need for improved annotation of disease alleles both in mutation databases and in the primary literature; some HGMD mutation data have been recategorized on the basis of the present findings, an iterative process that is both necessary and ongoing. Our estimates of deleterious-allele numbers are likely to be subject to both overcounting and undercounting. However, our current best mean estimates of ∼400 damaging variants and ∼2 bona fide disease mutations per individual are likely to increase rather than decrease as sequencing studies ascertain rare variants more effectively and as additional disease alleles are discovered.

We analyzed 40 single nucleotide polymorphism and 19 short tandem repeat Y-chromosomal markers in a large sample of 1,525 indigenous individuals from 14 populations in the Caucasus and 254 additional individuals representing potential source populations. We also employed a lexicostatistical approach to reconstruct the history of the languages of the North Caucasian family spoken by the Caucasus populations. We found a different major haplogroup to be prevalent in each of four sets of populations that occupy distinct geographic regions and belong to different linguistic branches. The haplogroup frequencies correlated with geography and, even more strongly, with language. Within haplogroups, a number of haplotype clusters were shown to be specific to individual populations and languages. The data suggested a direct origin of Caucasus male lineages from the Near East, followed by high levels of isolation, differentiation, and genetic drift in situ. Comparison of genetic and linguistic reconstructions covering the last few millennia showed striking correspondences between the topology and dates of the respective gene and language trees and with documented historical events. Overall, in the Caucasus region, unmatched levels of gene-language coevolution occurred within geographically isolated populations, probably due to its mountainous terrain.

The material presented here was used for a semester-long capstone project for a first semester freshman course entitled Mathematical Modeling and Introduction to Calculus. The goals for the students in this work were twofold: first, enable the students to gain insight into an actual problem that affects millions of people in the United States and worldwide; second, develop students' technical writing skills. The project was issued in three separate installments, each occurring after the requisite material was covered in the course. Each of the three sections was completed in groups of two or three students. [Supplementary materials are available for this article. Go to the publisher's online edition of PRIMUS for the following free supplemental resource(s): Appendix.]

We have evaluated the extent to which SNPs identified by genomewide surveys as showing unusually high levels of population differentiation in humans have experienced recent positive selection, starting from a set of 32 nonsynonymous SNPs in 27 genes highlighted by the HapMap1 project. These SNPs were genotyped again in the HapMap samples and in the Human Genome Diversity Project–Centre d'Etude du Polymorphisme Humain (HGDP–CEPH) panel of 52 populations representing worldwide diversity; extended haplotype homozygosity was investigated around all of them, and full resequence data were examined for 9 genes (5 from public sources and 4 from new data sets). For 7 of the genes, genotyping errors were responsible for an artifactual signal of high population differentiation and for 2, the population differentiation did not exceed our significance threshold. For the 18 genes with confirmed high population differentiation, 3 showed evidence of positive selection as measured by unusually extended haplotypes within a population, and 7 more did in between-population analyses. The 9 genes with resequence data included 7 with high population differentiation, and 5 showed evidence of positive selection on the haplotype carrying the nonsynonymous SNP from skewed allele frequency spectra; in addition, 2 showed evidence of positive selection on unrelated haplotypes. Thus, in humans, high population differentiation is (apart from technical artifacts) an effective way of enriching for recently selected genes, but is not an infallible pointer to recent positive selection supported by other lines of evidence.

Islam is the second most practiced religion in India, next to Hinduism. It is still unclear whether the spread of Islam in India has been only a cultural transformation or is associated with detectable levels of gene flow. To estimate the contribution of West Asian and Arabian admixture to Indian Muslims, we assessed genetic variation in mtDNA, Y-chromosomal and LCT/MCM6 markers in 472, 431 and 476 samples, respectively, representing six Muslim communities from different geographical regions of India. We found that most of the Indian Muslim populations received their major genetic input from geographically close non-Muslim populations. However, low levels of likely sub-Saharan African, Arabian and West Asian admixture were also observed among Indian Muslims in the form of L0a2a2 mtDNA and E1b1b1a and J(*)(xJ2) Y-chromosomal lineages. The distinction between Iranian and Arabian sources was difficult to make with mtDNA and the Y chromosome, as the estimates were highly correlated because of similar gene pool compositions in the sources. In contrast, the LCT/MCM6 locus, which shows a clear distinction between the two sources, enabled us to rule out significant gene flow from Arabia. Overall, our results support a model according to which the spread of Islam in India was predominantly cultural conversion associated with minor but still detectable levels of gene flow from outside, primarily from Iran and Central Asia, rather than directly from the Arabian Peninsula.

South Asia is home to more than 1.5 billion humans representing many diverse ethnicities, linguistic and religious groups and representing almost one-quarter of humanity. Modern humans arrived here soon after their departure from Africa approximately 50,000-70,000 years before present (YBP) and several subsequent human migrations and invasions, as well as the unique social structure of the region, have helped shape the pattern of genetic diversity currently observed in these populations. Over the last few decades population geneticists and molecular anthropologists have analyzed DNA variation in indigenous populations from this region in order to catalog their genetic relationships and histories. The emphasis is gradually shifting from the study of population origins to high resolution surveys of DNA variation to address issues of population stratification and genetic susceptibility or resistance to diseases in genome-wide association surveys. We present a historical overview of the genetic studies carried out on populations from this region in order to understand the influence of geographic, linguistic and religious factors on population diversity in this region, and discuss future prospects in light of developments in high throughput genotyping and next generation sequencing technologies.

We analyzed 67 short tandem repeat polymorphisms from the non-recombining part of the Y-chromosome (Y-STRs), including 49 rarely studied simple single-copy (ss)Y-STRs and 18 widely used Y-STRs, in 590 males from 51 populations belonging to 8 worldwide regions (HGDP-CEPH panel). Although autosomal DNA profiling provided no evidence for close relationship, we found 18 Y-STR haplotypes (defined by 67 Y-STRs) that were shared by two to five men in 13 worldwide populations, revealing high and widespread levels of cryptic male relatedness. Maximal (95.9%) haplotype resolution was achieved with the best 25 out of 67 Y-STRs in the global dataset, and with the best 3-16 markers in regional datasets (89.6-100% resolution). From the 49 rarely studied ssY-STRs, the 25 most informative markers were sufficient to reach the highest possible male lineage differentiation in the global (92.2% resolution), and 3-15 markers in the regional datasets (85.4-100%). Considerably lower haplotype resolutions were obtained with the three commonly used Y-STR sets (Minimal Haplotype, PowerPlex Y (R), and AmpFlSTR (R) Yfiler (R)). Six ssY-STRs (DYS481, DYS533, DYS549, DYS570, DYS576 and DYS643) were most informative to supplement the existing Y-STR kits for increasing haplotype resolution, or - together with additional ssY-STRs - as a new set for maximizing male lineage differentiation. Mutation rates of the 49 ssY-STRs were estimated from 403 meiotic transfers in deep-rooted pedigrees, and ranged from similar to 4.8 x 10(-4) for 31 ssY-STRs with no mutations observed to 1.3 x 10(-2) and 1.5 x 10(-2) for DYS570 and DYS576, respectively, the latter representing the highest mutation rates reported for human Y-STRs so far. Our findings thus demonstrate that ssY-STRs are useful for maximizing global and regional resolution of male lineages, either as a new set, or when added to commonly used Y-STR sets, and support their application to forensic, genealogical and anthropological studies. (C) 2009 Elsevier Ireland Ltd. All rights reserved.

Copy number variants (CNVs) underlie many aspects of human phenotypic diversity and provide the raw material for gene duplication and gene family expansion. However, our understanding of their evolutionary significance remains limited. We performed comparative genomic hybridization on a single human microarray platform to identify CNVs among the genomes of 30 humans and 30 chimpanzees as well as fixed copy number differences between species. We found that human and chimpanzee CNVs occur in orthologous genomic regions far more often than expected by chance and are strongly associated with the presence of highly homologous intrachromosomal segmental duplications. By adapting population genetic analyses for use with copy number data, we identified functional categories of genes that have likely evolved under purifying or positive selection for copy number changes. In particular, duplications and deletions of genes with inflammatory response and cell proliferation functions may have been fixed by positive selection and involved in the adaptive phenotypic differentiation of humans and chimpanzees.

We used a combination of amplified fragment length polymorphisms (AFLP) and morphological data from 272 individuals from 59 populations to investigate the species-level taxonomy of Carex roanensis and allied species. There were two taxonomic problems in this group: identifying the appropriate taxonomic status for Carex roanensis, and clarifying the distinctions (if any) between C. virescens and C. swanii. Principal coordinate analysis of the morphological data suggested four entities corresponding to C. aestivalis, C. roanensis, C. swanii, and C. virescens, but clear discrimination was not possible. In contrast, the AFLP data showed marked discontinuities among these four species, placing even morphological intermediates into one of four groups. Analysis of molecular variance revealed significant population differentiation within each species, but only C. virescens had any detectable differentiation between geographic regions. This study confirms the species-level distinction between the common and widespread taxa C. swanii and C. virescens, as well as that of the globally rare Appalachian endemic C. roanensis.

The Y-STR DYS19 is firmly established in the repertoire of Y-chromosomal markers used in forensic analysis yet is poorly understood at the molecular level, lying in a complex genomic environment and exhibiting null alleles, as well as duplications and occasional triplications in population samples. Here, we analyse three null alleles and 51 duplications and show that DYS19 can also be involved in inversion events, so that even its location within the short arm of the Y chromosome is uncertain. Deletion mapping in the three chromosomes carrying null alleles shows that their deletions are less than approximately 300 kb in size. Haplotypic analysis with binary markers shows that they belong to three different haplogroups and so represent independent events. In contrast, a collection of 51 DYS19 duplication chromosomes belong to only four haplogroups: two are singletons and may represent somatic mutation in lymphoblastoid cell lines, but two, in haplogroups G and C3c, represent founder lineages that have spread widely in Central Europe/West Asia and East Asia, respectively. Consideration of candidate mechanisms underlying both deletions and duplications provides no evidence for the involvement of non-allelic homologous recombination, and they are likely to represent sporadic events with low mutation rates. Understanding the basis and population distribution of these DYS19 alleles will aid in the utilisation and interpretation of profiles that contain them.