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Ludwig van Beethoven (1770–1827) remains among the most influential and popular classical music composers. Health problems significantly impacted his career as a composer and pianist, including progressive hearing loss, recurring gastrointestinal complaints, and liver disease. In 1802, Beethoven requested that following his death, his disease be described and made public. Medical biographers have since proposed numerous hypotheses, including many substantially heritable conditions. Here we attempt a genomic analysis of Beethoven in order to elucidate potential underlying genetic and infectious causes of his illnesses. We incorporated improvements in ancient DNA methods into existing protocols for ancient hair samples, enabling the sequencing of high-coverage genomes from small quantities of historical hair. We analyzed eight independently sourced locks of hair attributed to Beethoven, five of which originated from a single European male. We deemed these matching samples to be almost certainly authentic and sequenced Beethoven’s genome to 24-fold genomic coverage. Although we could not identify a genetic explanation for Beethoven's hearing disorder or gastrointestinal problems, we found that Beethoven had a genetic predisposition for liver disease. Metagenomic analyses revealed furthermore that Beethoven had a hepatitis B infection during at least the months prior to his death. Together with the genetic predisposition and his broadly accepted alcohol consumption, these present plausible explanations for Beethoven’s severe liver disease, which culminated in his death. Unexpectedly, an analysis of Y chromosomes sequenced from five living members of the Van Beethoven patrilineage revealed the occurrence of an extra-pair paternity event in Ludwig van Beethoven’s patrilineal ancestry. Introduction Results - Authentication of hair samples - Genetic variants associated with somatic disease - Hepatitis B virus DNA recovered from Beethoven’s hair Discussion - Authenticity of Beethoven’s genome - Comparison with living individuals’ genomes - Origins of Beethoven’s diseases - Hepatitis B virus DNA in Beethoven’s hair - Future directions

Next generation sequencing tests are used routinely as first-choice tests in the clinic. However, systematic performance comparing the results of exome sequencing as a single test replacing Sanger sequencing of targeted gene(s) is still lacking. Performance comparison data are critically important for clinical case management. In this study, we compared Sanger-sequencing results of 258 genes to those obtained from next generation sequencing (NGS) using two exome-sequencing enrichment kits: Agilent-SureSelectQXT and Illumina-Nextera. Sequencing was performed on leukocytes and buccal-derived DNA from a single individual, and all 258 genes were sequenced a total of 11 times (using different sequencing methods and DNA sources). Sanger sequencing was completed for all exons, including flanking ± 8 bp regions. For the 258 genes, NGS mean coverage was > 20 × for > 98 and > 91% of the regions targeted by SureSelect and Nextera, respectively. Overall, 449 variants were identified in at least one experiment, and 407/449 (90.6%) were detected by all. Of the 42 discordant variants, 23 were determined as true calls, summing-up to a truth set of 430 variants. Sensitivity of true-variant detection was 99% for Sanger sequencing and 97–100% for the NGS experiments. Mean false-positive rates were 3.7E-6 for Sanger sequencing, 2.5E-6 for SureSelect-NGS and 5.2E-6 for Nextera-NGS. Our findings suggest a high overall concordance between Sanger sequencing and NGS performances. Both methods demonstrated false-positive and false-negative calls. High clinical suspicion for a specific diagnosis should, therefore, override negative results of either Sanger sequencing or NGS.

The phylogenetic analysis of Y chromosomal haplogroup O2a-M95 was crucial to determine the nested structure of South Asian branches within the larger tree, predominantly present in East and Southeast Asia. However, it had previously been unclear that how many founders brought the haplogroup O2a-M95 to South Asia. On the basis of the updated Y chromosomal tree for haplogroup O2a-M95, we analysed 1437 male samples from South Asia for various novel downstream markers, carefully selected from the extant phylogenetic tree. With this increased resolution of genetic markers, we were able to identify at least three founders downstream to haplogroup O2a-M95, who are likely to have been associated with the dispersal of Austroasiatic languages to South Asia. The fourth founder was exclusively present amongst Tibeto-Burman speakers of Manipur and Bangladesh. In sum, our new results suggest the arrival of Austroasiatic languages in South Asia during last 5000 years.

Increased implementation of complex genetic technologies in clinical practice emphasizes the urgency of genomic literacy and proficiency for medical professionals. We evaluated our genomic education model. We assessed the 5-day, extended format program, encompassing lectures, videos, interactive tests, practice cases, and clinical exercises. Pre- and post questionnaires assessed knowledge change, using t-tests to compare groups. Satisfaction on program completion and after 3 years were evaluated. Implementation in other centers determined acceptability. During 2012–2018, 774 clinicians from multiple disciplines and career stages attended 35 programs; 334 (43%) attended the 5-day extended format. Evaluations showed significant improvement of genomic literacy (mean 15.05/100 points, p

Mutations in the gene HSD17B3 encoding the 17-beta hydroxysteroid dehydrogenase 3 enzyme cause testosterone insufficiency leading to XY disorders of sex development. In this study the clinical and molecular characteristics of three patients from consanguineous families are elucidated. We identified three patients from two unrelated families with XY DSD and a novel homozygous HSD17B3:c. 673G>A mutation. The effect of the mutation on splicing was determined in RNA extracted from the testis of one patient. Three patients presented at ages 0.1, 8 and 0.7 years with ambiguous genitalia and an XY Karyotype. Endocrine workup showed normal cortisol and mineralocorticoid levels with a low testosterone/androstenedione ratio. Whole-exome sequencing, carried out in the first family, revealed a homozygous novel mutation in the HSD17B3 gene: c. 673G>A, p. V225M. The same mutation was found by Sanger sequencing in the third unrelated patient. Haplotype analysis of a 4 Mb region surrounding the HSD17B3 gene on chromosome 9 revealed that the mutation resides on the same allele in all three patients. The mutation, being the first nucleic acid on exon 10, affects splicing and causes exon 10 skipping in one of our patients’ testes. The novel homozygous c. 673G>A, p. V225M mutation in the 17HSDB3 gene is likely a founder mutation and causes severe XY-DSD. It changes a conserved amino acid residue, and also alters 17HSDB3 gene transcription by causing skipping of exon 10, thereby contributing to an imbalance in the relevant protein isoforms and consequently, significant decreased 17HDSB3 enzymatic activity.

Immigration from one cultural milieu to another has been associated with a greater risk for incident cardio-metabolic morbidity among adults. In this nationwide, population-based, cross-sectional study of data recorded from 1992 to 2016, we assessed the association between body mass index and blood pressure levels among adolescent immigrants, aged 16 to 19 years, of Ethiopian origin, and their secular trend of overweight and obesity. Adolescents of Ethiopian origin were classified as Israeli-born (n=16 153) or immigrants (N=23 487), with stratification by age at immigration. Adolescents whose fathers were at least 3 generations in Israel (n=277 789) served as a comparative group. Hypertensive-range blood pressure values adjusted for age, sex, and height served as outcome. Among adolescents of Ethiopian origin, overweight and obesity (body mass index ≥85th percentile), increased by 2.5 and 4-fold in males and females, respectively, during the study period, compared with a 1.5-fold increase among native Israeli-born males and females. The odds for hypertensive-range measurements increased with the length of residence in Israel: 7.3%, 10.6%, and 14.4% among males who immigrated at ages 12 to 19, 6 to 11.9, and 0 to 5.9 years, respectively; and 11.5%, 16.7%, and 19.3%, respectively, among females. Israeli-born Ethiopians had a significantly higher risk for hypertensive-range measurements at any body mass index level compared with native Israeli-born examinees, after adjusting for sociodemographic factors and health status. In conclusion, among Ethiopian Israeli adolescents, abnormal blood pressure correlates directly with the time-lapse since immigration. Immigrant populations require targeted surveillance and appropriate intervention.

The presence of genomic signatures of Eurasian origin in contemporary Ethiopians has been reported by several authors and estimated to have arrived in the area from 3000 years ago. Several studies reported plausible source populations for such a signature, using haplotype based methods on modern data or single-site methods on modern or ancient data. These studies did not reach a consensus and suggested an Anatolian or Sardinia-like proxy, broadly Levantine or Neolithic Levantine as possible sources. We demonstrate, however, that the deeply divergent, autochthonous African component which accounts for ~50% of most contemporary Ethiopian genomes, affects the overall allele frequency spectrum to an extent that makes it hard to control for it and, at once, to discern between subtly different, yet important, Eurasian sources (such as Anatolian or Levant Neolithic ones). Here we re-assess pattern of allele sharing between the Eurasian component of Ethiopians (here called "NAF" for Non African) and ancient and modern proxies. Our results unveil a genomic legacy that may connect the Eurasian genetic component of contemporary Ethiopians with Sea People and with population movements that affected the Mediterranean area and the Levant after the fall of the Minoan civilization. ispartof: SCIENTIFIC REPORTS vol:9 issue:1 ispartof: location:England status: published

Background A Southwest Asian origin and dispersal to North Africa in the Early Upper Palaeolithic era has been inferred in previous studies for mtDNA haplogroups M1 and U6. Both haplogroups have been proposed to show similar geographic patterns and shared demographic histories. Results We report here 24 M1 and 33 U6 new complete mtDNA sequences that allow us to refine the existing phylogeny of these haplogroups. The resulting phylogenetic information was used to genotype a further 131 M1 and 91 U6 samples to determine the geographic spread of their sub-clades. No southwest Asian specific clades for M1 or U6 were discovered. U6 and M1 frequencies in North Africa, the Middle East and Europe do not follow similar patterns, and their sub-clade divisions do not appear to be compatible with their shared history reaching back to the Early Upper Palaeolithic. The Bayesian Skyline Plots testify to non-overlapping phases of expansion, and the haplogroups’ phylogenies suggest that there are U6 sub-clades that expanded earlier than those in M1. Some M1 and U6 sub-clades could be linked with certain events. For example, U6a1 and M1b, with their coalescent ages of ~20,000–22,000 years ago and earliest inferred expansion in northwest Africa, could coincide with the flourishing of the Iberomaurusian industry, whilst U6b and M1b1 appeared at the time of the Capsian culture. Conclusions Our high-resolution phylogenetic dissection of both haplogroups and coalescent time assessments suggest that the extant main branching pattern of both haplogroups arose and diversified in the mid-later Upper Palaeolithic, with some sub-clades concomitantly with the expansion of the Iberomaurusian industry. Carriers of these maternal lineages have been later absorbed into and diversified further during the spread of Afro-Asiatic languages in North and East Africa.

The human WW Domain Containing Oxidoreductase (WWOX) gene was originally described as a tumor suppressor gene. However, recent reports have demonstrated its cardinal role in the pathogenesis of central nervous systems disorders such as epileptic encephalopathy, intellectual disability, and spinocerebellar ataxia. We report on six patients from three unrelated families of full or partial Yemenite Jewish ancestry exhibiting early infantile epileptic encephalopathy and profound developmental delay. Importantly, four patients demonstrated facial dysmorphism. Exome sequencing revealed that four of the patients were homozygous for a novel WWOX c.517-2A > G splice-site variant and two were compound heterozygous for this variant and a novel c.689A > C, p.Gln230Pro missense variant. Complementary DNA sequencing demonstrated that the WWOX c.517-2A > G splice-site variant causes skipping of exon six. A carrier rate of 1:177 was found among Yemenite Jews. We provide the first detailed description of patients harboring a splice-site variant in the WWOX gene and propose that the clinical synopsis of WWOX related epileptic encephalopathy should be broadened to include facial dysmorphism. The increased frequency of the c.517-2A > G splice-site variant among Yemenite Jews coupled with the severity of the phenotype makes it a candidate for inclusion in expanded preconception screening programs.

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Human Y chromosome haplogroup J1-M267 is a common male lineage in West Asia. One high-frequency region—encompassing the Arabian Peninsula, southern Mesopotamia, and the southern Levant—resides ~ 2000 km away from the other one found in the Caucasus. The region between them, although has a lower frequency, nevertheless demonstrates high genetic diversity. Studies associate this haplogroup with the spread of farming from the Fertile Crescent to Europe, the spread of mobile pastoralism in the desert regions of the Arabian Peninsula, the history of the Jews, and the spread of Islam. Here, we study past human male demography in West Asia with 172 high-coverage whole Y chromosome sequences and 889 genotyped samples of haplogroup J1-M267. We show that this haplogroup evolved ~ 20,000 years ago somewhere in northwestern Iran, the Caucasus, the Armenian Highland, and northern Mesopotamia. The major branch—J1a1a1-P58—evolved during the early Holocene ~ 9500 years ago somewhere in the Arabian Peninsula, the Levant, and southern Mesopotamia. Haplogroup J1-M267 expanded during the Chalcolithic, the Bronze Age, and the Iron Age. Most probably, the spread of Afro-Asiatic languages, the spread of mobile pastoralism in the arid zones, or both of these events together explain the distribution of haplogroup J1-M267 we see today in the southern regions of West Asia.

The most frequent Y-chromosomal (chrY) haplogroups in northern and eastern Europe (NEE) are well-known and thoroughly characterised. Yet a considerable number of men in every population carry rare paternal lineages with estimated frequencies around 5%. So far, limited sample-sizes and insufficient resolution of genotyping have obstructed a truly comprehensive look into the variety of rare paternal lineages segregating within populations and potential signals of population history that such lineages might convey. Here we harness the power of massive re-sequencing of human Y chromosomes to identify previously unknown population-specific clusters among rare paternal lineages in NEE. We construct dated phylogenies for haplogroups E2-M215, J2-M172, G-M201 and Q-M242 on the basis of 421 (of them 282 novel) high-coverage chrY sequences collected from large-scale databases focusing on populations of NEE. Within these otherwise rare haplogroups we disclose lineages that began to radiate ~1-3 thousand years ago in Estonia and Sweden and reveal male phylogenetic patterns testifying of comparatively recent local demographic expansions. Conversely, haplogroup Q lineages bear evidence of ancient Siberian influence lingering in the modern paternal gene pool of northern Europe. We assess the possible direction of influx of ancestral carriers for some of these male lineages. In addition, we demonstrate the congruency of paternal haplogroup composition of our dataset with two independent population-based cohorts from Estonia and Sweden.

Next generation sequencing tests are used routinely as first-choice tests in the clinic. However, systematic performance comparing the results of exome sequencing as a single test replacing Sanger sequencing of targeted gene(s) is still lacking. Performance comparison data are critically important for clinical case management. In this study, we compared Sanger-sequencing results of 258 genes to those obtained from next generation sequencing (NGS) using two exome-sequencing enrichment kits: Agilent-SureSelectQXT and Illumina-Nextera. Sequencing was performed on leukocytes and buccal-derived DNA from a single individual, and all 258 genes were sequenced a total of 11 times (using different sequencing methods and DNA sources). Sanger sequencing was completed for all exons, including flanking ± 8 bp regions. For the 258 genes, NGS mean coverage was 20 × for 98 and 91% of the regions targeted by SureSelect and Nextera, respectively. Overall, 449 variants were identified in at least one experiment, and 407/449 (90.6%) were detected by all. Of the 42 discordant variants, 23 were determined as true calls, summing-up to a truth set of 430 variants. Sensitivity of true-variant detection was 99% for Sanger sequencing and 97-100% for the NGS experiments. Mean false-positive rates were 3.7E-6 for Sanger sequencing, 2.5E-6 for SureSelect-NGS and 5.2E-6 for Nextera-NGS. Our findings suggest a high overall concordance between Sanger sequencing and NGS performances. Both methods demonstrated false-positive and false-negative calls. High clinical suspicion for a specific diagnosis should, therefore, override negative results of either Sanger sequencing or NGS.

Systematic performance comparing the results of exome-sequencing as a single test replacing Sanger-sequencing of targeted gene(s) is still lacking. In this study we compared Sanger-sequencing results of 258 genes to those obtained from next generation sequencing (NGS) using two exome-sequencing enrichment kits: Agilent-SureSelectQXT and Illumina-Nextera. Sequencing was performed on leukocytes and buccal-derived DNA from a single individual, and all 258 genes were sequenced a total of 11 times (using different sequencing methods and DNA sources). Sanger-sequencing was completed for all exons, including flanking ±8bp regions. For the 258 genes, NGS mean coverage was >20x for >98% and >91% of the regions targeted by SureSelect and Nextera, respectively. Overall, 449 variants were identified in at least one experiment, and 407/449 (90.6%) were detected by all. Of the 42 discordant variants, 23 were determined as true calls, summing-up to a truth set of 430 variants. Sensitivity of true-variant detection was 99% for Sanger-sequencing and 97%-100% for the NGS experiments. Mean false-positive rates were 3.7E-6 for Sanger-sequencing, 2.5E-6 for SureSelect-NGS and 5.2E-6 for Nextera-NGS. Our findings suggest a high overall concordance between Sanger-sequencing and NGS. Both methods demonstrated false positive and false negative calls and similar performances. Consequently, high clinical suspicion for a specific diagnosis should override negative results of either Sanger-sequencing or NGS.

Background We assessed in a nationwide cohort the association between adolescent BMI and early-onset ( Methods Normoglycemic adolescents (range 16–20 years old), including 93,806 native Israelis (≥ 3rd generation in Israel) and 27,684 Israelis of Ethiopian origin, were medically assessed for military service between 1996 and 2011. Weight and height were measured. Data were linked to the Israeli National Diabetes Registry. Incident type 2 diabetes by December 31, 2016 was the outcome. Cox regression models stratified by sex and BMI categories were applied. Results 226 (0.29%) men and 79 (0.18%) women developed diabetes during 992,980 and 530,814 person-years follow-up, respectively, at a mean age of 30.4 and 27.4 years, respectively. Among native Israeli men with normal and high (overweight and obese) BMI, diabetes incidence was 9.5 and 62.0 (per 105 person-years), respectively. The respective incidences were 46.9 and 112.3 among men of Ethiopian origin. After adjustment for sociodemographic confounders, the hazard ratios for type 2 diabetes among Ethiopian men with normal and high BMI were 3.4 (2.3–5.1) and 15.8 (8.3–30.3) respectively, compared to third-generation Israelis with normal BMI. When this analysis was limited to Israeli-born Ethiopian men, the hazard ratios were 4.4 (1.7–11.4) and 29.1 (12.9–70.6), respectively. Results persisted when immigrants of other white Caucasian origin were the reference; and among women with normal, but not high, BMI. Conclusions Ethiopian origin is a risk factor for early-onset type 2 diabetes among young men at any BMI, and may require selective interventions.

Increased implementation of complex genetic technologies in clinical practice emphasizes the urgency of genomic literacy and proficiency for medical professionals. We evaluated our genomic education model.We assessed the 5-day, extended format program, encompassing lectures, videos, interactive tests, practice cases, and clinical exercises. Pre- and post questionnaires assessed knowledge change, using t-tests to compare groups. Satisfaction on program completion and after 3 years were evaluated. Implementation in other centers determined acceptability.During 2012-2018, 774 clinicians from multiple disciplines and career stages attended 35 programs; 334 (43%) attended the 5-day extended format. Evaluations showed significant improvement of genomic literacy (mean 15.05/100 points, p 0.001). Residents initially had higher scores than specialists (pre: 66.3 ± 17.3 vs. 58.7 ± 16.6, respectively, p = 0.002); both significantly improved, with specialists "catching up" (post: 79.1 ± 17.2 vs. 75.7 ± 15.9, nonsignificant (NS)); there was a similar trend between fellows and subspecialists (pre: 70 ± 18 vs. 59.4 ± 16.4, respectively, p = 0.007; post: 78.6 ± 16.4 vs. 73.2 ± 17.7, respectively, NS). Younger specialists (≤10 years residency) had significantly higher pre- and post scores. Absolute improvement in scores did not depend on medical specialties.Our program is effective in improving genomics literacy for clinicians, irrespective of career length or expertise, and could be a model for improving skills in practical genomics for all medical professionals.

Mutations in the gene HSD17B3 encoding the 17-beta hydroxysteroid dehydrogenase 3 enzyme cause testosterone insufficiency leading to XY disorders of sex development. In this study the clinical and molecular characteristics of three patients from consanguineous families are elucidated.We identified three patients from two unrelated families with XY DSD and a novel homozygous HSD17B3:c. 673GA mutation. The effect of the mutation on splicing was determined in RNA extracted from the testis of one patient.Three patients presented at ages 0.1, 8 and 0.7 years with ambiguous genitalia and an XY Karyotype. Endocrine workup showed normal cortisol and mineralocorticoid levels with a low testosterone/androstenedione ratio. Whole-exome sequencing, carried out in the first family, revealed a homozygous novel mutation in the HSD17B3 gene: c. 673GA, p. V225M. The same mutation was found by Sanger sequencing in the third unrelated patient. Haplotype analysis of a 4 Mb region surrounding the HSD17B3 gene on chromosome 9 revealed that the mutation resides on the same allele in all three patients. The mutation, being the first nucleic acid on exon 10, affects splicing and causes exon 10 skipping in one of our patients' testes.The novel homozygous c. 673GA, p. V225M mutation in the 17HSDB3 gene is likely a founder mutation and causes severe XY-DSD. It changes a conserved amino acid residue, and also alters 17HSDB3 gene transcription by causing skipping of exon 10, thereby contributing to an imbalance in the relevant protein isoforms and consequently, significant decreased 17HDSB3 enzymatic activity.

Background Preconception carrier screening for cystic fibrosis (CF) is usually performed using ethnically targeted panels of selected mutations. This has been recently challenged by the use of expanded, ethnically indifferent, pan-population panels. Israel is characterized by genetically heterogeneous populations carrying a wide range of CFTR mutations. To assess the potential of expanding the current Israeli preconception screening program, we sought the subset of molecularly unresolved CF patients listed in the Israeli CF data registry comprising ~650 patients. Methods An Israeli nationwide genotyping of 152 CF cases, representing 176 patients lacking molecular diagnosis, was conducted. Molecular analysis included Sanger sequencing for all exons and splice sites, multiplex ligation probe amplification (MLPA), and next-generation sequencing of the poly-T/TG tracts. Results We identified 54 different mutations, of which only 16 overlapped the 22 mutations included in the Israeli preconception screening program. A total of 29/54 (53.7%) mutations were already listed as CF causing by the CFTR2 database, and only 4/54 (7.4%) were novel. Molecular diagnosis was reached in 78/152 (51.3%) cases. Prenatal diagnosis of 24/78 (30.8%) cases could have been achieved by including all CFTR2-causing mutations in the Israeli panel. Conclusions Our data reveal an overwhelming hidden abundance of CFTR gene mutations suggesting that expanded preconception carrier screening might achieve higher preconception detection rates.

Expanded preconception carrier screening (ECS) identifies at-risk couples (ARCs) for multiple diseases. ECS reports currently include only pathogenic/likely pathogenic variants (P/LPVs). Variants of unknown significance (VUS) are not reported, unlike genomic or chromosomal array test results in other post/prenatal settings. Couples who are P/LP and VUS carriers (P/LP*VUS) may be at risk, particularly in genes with high P/LP carrier rates. We examined the possible contribution of P/LP*cVUS (coding, nonsynonymous VUS) matings to ECS yield in an Ashkenazi Jewish cohort, a population with well-established preconception screening.We analyzed 672 Ashkenazi Jewish genome sequences (225,456 virtual matings) for variants in three different gene sets and calculated the rates of P/LP*P/LP and P/LP*cVUS matings.Across 180 genes, we identified 4671 variants: 144 (3.1%) P/LP and 1963 (42%) VUS. Across gene sets, the proportion of P/LP*P/LP and P/LP*cVUS ARCs was 2.7-3.8% and 6.8-7.5%, respectively.Disregarding VUS in ECS may miss ARCs. Even if only 10% of couples currently classified as P/LP*cVUS are ultimately reclassified as P/LP*P/LP, ECS yield would increase by ≈20%. While current understanding of VUS precludes VUS reporting in ECS, these findings underscore the importance of VUS reclassification. This will crucially depend on enlarging population frequency databases, especially of affected individuals.

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Objectives The gene encoding glucose transporter 3 (GLUT3, SLC2A3) is present in the human population at variable copy number. An overt disease phenotype of SLC2A3 copy number variants has not been reported; however, deletion of SLC2A3 has been previously reported to protect carriers from rheumatoid arthritis, implicating GLUT3 as a therapeutic target in rheumatoid arthritis. Here we aim to perform functional analysis of GLUT3 copy number variants in immune cells, and test the reported protective association of the GLUT3 copy number variants for rheumatoid arthritis in a genetic replication study. Methods Cells from genotyped healthy controls were analyzed for SLC2A3/GLUT3 expression and glycolysis capacity. We genotyped the SLC2A3 copy number variant in four independent cohorts of rheumatoid arthritis and controls and one cohort of multiple sclerosis and controls. Results Heterozygous deletion of SLC2A3 correlates directly with expression levels of GLUT3 and influences glycolysis rates in the human immune system. The frequency of the SLC2A3 copy number variant is not different between rheumatoid arthritis, multiple sclerosis and control groups. Conclusions Despite a robust SLC2A3 gene copy number dependent phenotype, our study of large groups of rheumatoid arthritis cases and controls provides no evidence for rheumatoid arthritis disease protection in deletion carriers. These data emphasize the importance of well powered replication studies to confirm or refute genetic associations, particularly for relatively rare variants., Highlights • T cell and macrophage expression of SLC2A3/GLUT3 correlates to SLC2A3 gene copy number in a dose dependent manner. • Glycolysis rates are reduced in individuals harboring a deletion of the GLUT3 gene SLC2A3 • Deletion of SLC2A3 is not associated with protection from rheumatoid arthritis • Deletion of SLC2A3 is not associated with risk for multiple sclerosis • GLUT3 is not a viable therapeutic target for RA as previously proposed based on a protective association of SLC2A3 deletion.

Surrounded by speakers of Indo-European, Dravidian and Tibeto-Burman languages, around 11 million Munda (a branch of Austroasiatic language family) speakers live in the densely populated and genetically diverse South Asia. Their genetic makeup holds components characteristic of South Asians as well as Southeast Asians. The admixture time between these components has been previously estimated on the basis of archaeology, linguistics and uniparental markers. Using genome-wide genotype data of 102 Munda speakers and contextual data from South and Southeast Asia, we retrieved admixture dates between 2000-3800 years ago for different populations of Munda. The best modern proxies for the source populations for the admixture with proportions 0.29/0.71 are Lao people from Laos and Dravidian speakers from Kerala in India. The South Asian population(s), with whom the incoming Southeast Asians intermixed, had a smaller proportion of West Eurasian genetic component than contemporary proxies. Somewhat surprisingly Malaysian Peninsular tribes rather than the geographically closer Austroasiatic languages speakers like Vietnamese and Cambodians show highest sharing of IBD segments with the Munda. In addition, we affirmed that the grouping of the Munda speakers into North and South Munda based on linguistics is in concordance with genome-wide data. ispartof: SCIENTIFIC REPORTS vol:9 issue:1 ispartof: location:England status: published

In the vast majority of pediatric patients with dilated cardiomyopathy, the specific etiology is unknown. Studies on families with dilated cardiomyopathy have exemplified the role of genetic factors in cardiomyopathy etiology. In this study, we applied whole-exome sequencing to members of a non-consanguineous family affected by a previously unreported congenital dilated cardiomyopathy syndrome necessitating early-onset heart transplant. Exome analysis identified compound heterozygous variants in the FLNC gene. Histological analysis of the cardiac muscle demonstrated marked sarcomeric and myofibrillar abnormalities, and immunohistochemical staining demonstrated the presence of Filamin C aggregates in cardiac myocytes. We conclude that biallelic variants in FLNC can cause congenital dilated cardiomyopathy. As the associated clinical features of affected patients are mild, and can be easily overlooked, testing for FLNC should be considered in children presenting with dilated cardiomyopathy.

Pathogenic variants in the NONO gene have been most recently implicated in X-linked intellectual disability syndrome. This observation has been supported by studies of NONO-deficient mice showing that NONO has an important role in regulating inhibitory synaptic activity. Thus far, the phenotypic spectrum of affected patients remains limited. We applied whole exome sequencing to members of a family in which the proband was presented with a complex phenotype consisting of developmental delay, dysmorphism, and non-compaction cardiomyopathy. Exome analysis identified a novel de novo splice-site variant c.1171+1G>T in exon 11 of NONO gene that is suspected to abolish the donor splicing site. Thus, we propose that the phenotypic spectrum of NONO-related disorder is much broader than described and that pathogenic variants in NONO cause a recognizable phenotype.

BackgroundMutations in the NCF1 gene that encodes p47phox, a subunit of the NADPH oxidase complex, cause chronic granulomatous disease (CGD). In Kavkazi Jews, a c.579G>A (p.Trp193Ter) mutation in NCF1 is frequently found, leading to CGD. The same mutation is found in about 1% of Ashkenazi Jews, although Ashkenazi CGD patients with this mutation have never been described.MethodsWe used Sanger sequencing, multiplex ligation-dependent probe amplification (MLPA), gene scan analysis and Ion Torrent Next Generation Sequencing for genetic analysis, and measured NADPH oxidase activity and p47phox expression.ResultsIn an Ashkenazi couple expecting a baby, both parents were found to be heterozygotes for this mutation, as was the fetus. However, segregation analysis in the extended family was consistent with the fetus inheriting both carrier alleles from the parents. MLPA indicated four complete NCF1 genes in the fetus and three in each parent. Gene sequencing confirmed these results. Analysis of fetal leucocytes obtained by cordocentesis revealed substantial oxidase activity with three different assays, which was confirmed after birth. In six additional Ashkenazi carriers of the NCF1 c.579G>A mutation, we found five individuals with three complete NCF1 genes of which one was mutated (like the parents), and one individual with in addition a fusion gene of NCF1 with a pseudogene.ConclusionThese results point to the existence of a ‘false-carrier’ state in Ashkenazi Jews and have wide implications regarding pre-pregnancy screening in this and other population groups.

The rugged topography of the Himalayan region has hindered large-scale human migrations, population admixture and assimilation. Such complexity in geographical structure might have facilitated the existence of several small isolated communities in this region. We have genotyped about 850,000 autosomal markers among 35 individuals belonging to the four major populations inhabiting the Himalaya and adjoining regions. In addition, we have genotyped 794 individuals belonging to 16 ethnic groups from the same region, for uniparental (mitochondrial and Y chromosomal DNA) markers. Our results in the light of various statistical analyses suggest a closer link of the Himalayan and adjoining populations to East Asia than their immediate geographical neighbours in South Asia. Allele frequency-based analyses likely support the existence of a specific ancestry component in the Himalayan and adjoining populations. The admixture time estimate suggests a recent westward migration of populations living to the East of the Himalaya. Furthermore, the uniparental marker analysis among the Himalayan and adjoining populations reveal the presence of East, Southeast and South Asian genetic signatures. Interestingly, we observed an antagonistic association of Y chromosomal haplogroups O3 and D clines with the longitudinal distance. Thus, we summarise that studying the Himalayan and adjoining populations is essential for a comprehensive reconstruction of the human evolutionary and ethnolinguistic history of eastern Eurasia.

We describe a Bedouin family with a novel autosomal recessive syndrome characterized by dilated cardiomyopathy and septo-optic dysplasia. Genetic analysis revealed a homozygous missense mutation in TAX1BP3, which encodes a small PDZ domain containing protein implicated in regulation of the Wnt/β-catenin signaling pathway, as the causative mutation. The mutation affects a conserved residue located at the core of TAX1BP3 binding pocket and is predicted to impair the nature of a crucial hydrophobic patch, thereby interrupting the structure and stability of the protein, and its ability to interact with other proteins. TAX1BP3 is highly expressed in heart and brain and consistent with the clinical findings observed in our patients; a knockdown of TAX1BP3 causes elongation defects, enlarged pericard, and enlarged head structures in zebrafish embryos. Thus, we describe a new genetic disorder that expands the monogenic cardiomyopathy disease spectrum and suggests that TAX1BP3 is essential for heart and brain development.

Lissencephaly comprises a heterogeneous group of developmental brain disorders of varying severity, involving abnormal cortical gyration. We studied a highly consanguineous Israeli Moslem family with a lethal form of autosomal recessive lissencephaly with cerebellar hypoplasia (LCH). Using microarray-based homozygosity mapping in the reported family, combined with whole exome sequencing in one affected infant, we identified a homozygous splice site mutation g.IVS8+1G>A in cyclin-dependent kinase 5 (CDK5), causing complete skipping of exon 8, and leading to a frame shift and premature stop codon (p.V162SfsX19). The mutation co-segregated with the disease phenotype in all 29 study participants (4 patients and 25 healthy relatives), and was not identified in 200 ethnically matched control chromosomes. The p.V162SfsX19 mutation causes lack of endogenous CDK5 expression in affected dermal fibroblasts and brain tissue at the mRNA and protein levels, consistent with nonsense-mediated mRNA decay. Functional analysis of the p.V162SfsX19 mutation, using a yeast complementation assay, showed loss-of-function of the mutant CDK5 gene product, thereby implicating its role in the pathogenesis of autosomal recessive LCH in the studied family.

Objectives: Recent studies have highlighted the potential of analyses of genomic sharing to produce insight into the demographic processes affecting human populations. We study runs of homozygosity (ROH) in 18 Jewish populations, examining these groups in relation to 123 non-Jewish populations sampled worldwide. Methods: By sorting ROH into 3 length classes (short, intermediate, and long), we evaluate the impact of demographic processes on genomic patterns in Jewish populations. Results: We find that the portion of the genome appearing in long ROH - the length class most directly related to recent consanguinity - closely accords with data gathered from interviews during the 1950s on frequencies of consanguineous unions in various Jewish groups. Conclusion: The high correlation between 1950s consanguinity levels and coverage by long ROH explains differences across populations in ROH patterns. The dissection of ROH into length classes and the comparison to consanguinity data assist in understanding a number of additional phenomena, including similarities of Jewish populations to Middle Eastern, European, and Central and South Asian non-Jewish populations in short ROH patterns, relative lengths of identity-by-descent tracts in different Jewish groups, and the “population isolate” status of the Ashkenazi Jews.

Approximately 300,000 men around the globe self-identify as Ashkenazi Levites, of whom two thirds were previously shown to descend from a single male. The paucity of whole Y-chromosome sequences precluded conclusive identification of this ancestor’s age, geographic origin and migration patterns. Here, we report the variation of 486 Y-chromosomes within the Ashkenazi and non-Ashkenazi Levite R1a clade, other Ashkenazi Jewish paternal lineages, as well as non-Levite Jewish and non-Jewish R1a samples. Cumulatively, the emerging profile is of a Middle Eastern ancestor, self-affiliating as Levite, and carrying the highly resolved R1a-Y2619 lineage, which was likely a minor haplogroup among the Hebrews. A star-like phylogeny, coalescing similarly to other Ashkenazi paternal lineages, ~1,743 ybp, suggests it to be one of the Ashkenazi paternal founders; to have expanded as part of the overall Ashkenazi demographic expansion, without special relation to the Levite affiliation; and to have subsequently spread to non-Ashkenazi Levites.

Human mitochondrial DNA haplogroup U is among the initial maternal founders in Southwest Asia and Europe and one that best indicates matrilineal genetic continuity between late Pleistocene hunter-gatherer groups and present-day populations of Europe. While most haplogroup U subclades are older than 30 thousand years, the comparatively recent coalescence time of the extant variation of haplogroup U7 (∼16-19 thousand years ago) suggests that its current distribution is the consequence of more recent dispersal events, despite its wide geographical range across Europe, the Near East and South Asia. Here we report 267 new U7 mitogenomes that - analysed alongside 100 published ones - enable us to discern at least two distinct temporal phases of dispersal, both of which most likely emanated from the Near East. The earlier one began prior to the Holocene (∼11.5 thousand years ago) towards South Asia, while the later dispersal took place more recently towards Mediterranean Europe during the Neolithic (∼8 thousand years ago). These findings imply that the carriers of haplogroup U7 spread to South Asia and Europe before the suggested Bronze Age expansion of Indo-European languages from the Pontic-Caspian Steppe region., 0, SCOPUS: ar.j, info:eu-repo/semantics/published

Primary ovarian insufficiency (POI) is caused by ovarian follicle depletion or follicle dysfunction. The phenotypic spectrum ranges from absence of pubertal maturation to early menopause. Genes involved in essential steps in chromosome synapsis and recombination during meiosis, such as synaptonemal complex central element 1 (SYCE1), have been shown to cause POI in animal models. We describe for the first time a homozygous mutation in SYCE1 in humans.To identify the genetic cause of POI in an Israeli Arab family with a consanguineous pedigree.A family-based genetic study conducted at a tertiary medical center.Two daughters of consanguineous parents (first cousins) from a 13-member family were diagnosed with POI. Genotyping was performed in the index patients, their parents, and four unaffected siblings.DNA from the affected sisters was subjected to whole-exome sequencing. The genotypes of interest were confirmed and genotypes of the additional family members were determined by Sanger sequencing. Genotyping was also performed in 90 ethnically matched control individuals.A nonsense homozygous mutation (c.613CT) was identified in the SYCE1 gene in both affected sisters. The parents and three brothers were heterozygous for the mutation, and an unaffected sister did not carry the mutation. The mutation was not identified in the DNA samples from the 90 control subjects.Given the known function of the SYCE1 gene, we suggest that the nonsense mutation identified accounts for the POI phenotype. These results highlight the importance of the synaptonemal complex and meiosis in ovarian function.

Huntington disease (HD), an autosomal dominant disorder involving HTT, is characterized by chorea, psychiatric illness and cognitive decline. Diagnosis and age of onset depend on the degree of expansion of the trinucleotide CAG repeat within the gene. The prevalence of HD is known for Europeans but has not been studied in the Israeli population. Between 2006 and 2011 we diagnosed in our adult genetics clinic ten HD probands, nine of whom were Caucasus Jews (CJ) (Azerbaijani), and one Ashkenazi Jewish. We performed haplotype analysis to look for evidence of a founder mutation, and found that of the nine CJ, eight shared the same haplotype that was compatible with the A1 haplogroup. We calculated the coalescence age of the mutation to be between 80 and 150 years. Ninety percent of our HD patients are CJ, as are 27% of the HD patients in Israel, although the CJ comprise only 1.4% of the Israeli population. Our findings suggest a higher prevalence of HD among CJ compared to the general Israeli population and are consistent with a recent founder mutation. We recommend a higher degree of suspicion for HD in CJ with subtle clinical findings.

Congenital pancreatic lipase (PNLIP) deficiency is a rare monoenzymatic form of exocrine pancreatic failure characterized by decreased absorption of dietary fat and greasy voluminous stools, but apparent normal development and an overall good state of health. While considered to be an autosomal recessive state affecting a few dozens of individuals world-wide and involving the PNLIP gene, no causative mutations for this phenotype were so far reported. Here, we report the identification of the homozygote missense mutation, Thr221Met [c.662C>T], in two brothers from a consanguineous family of Arab ancestry. The observed genotypes among the family members were concordant with an autosomal recessive mode of inheritance but moreover a clear segregation between the genotype state and the serum PNLIP activity was evident. Based on biophysical computational tools, we suggest the mutation disrupts the protein's stability and impairs its normal function. Although the role of PNLIP is well established, our observations provide genetic evidence that PNLIP mutations are causative for this phenotype.

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.

SummaryWhole-exome sequencing for clinical applications is now an integral part of medical genetics practice. Though most studies are performed in order to establish diagnoses in individuals with rare and clinically unrecognizable disorders, due to the constantly decreasing costs and commercial availability, whole-exome sequencing has gradually become the initial tool to study patients with clinically recognized disorders when more than one gene is responsible for the phenotype or in complex phenotypes, when variants in more than one gene can be the cause for the disease. Here we report a patient presenting with a complex phenotype consisting of severe, adult-onset, dilated cardiomyopathy, hearing loss and developmental delay, in which exome sequencing revealed two genetic variants that are inherited from a healthy mother: a novel missense variant in the CASK gene, mutations in which cause a spectrum of neurocognitive manifestations, and a second variant, in MYBPC3, that is associated with hereditary cardiomyopathy. We conclude that although the potential for co-occurrence of rare diseases is higher when analyzing undefined phenotypes in consanguineous families, it should also be given consideration in the genetic evaluation of complex phenotypes in non-consanguineous families.

The paternal haplogroup (hg) N is distributed from southeast Asia to eastern Europe. The demographic processes that have shaped the vast extent of this major Y chromosome lineage across numerous linguistically and autosomally divergent populations have previously been unresolved. On the basis of 94 high-coverage re-sequenced Y chromosomes, we establish and date a detailed hg N phylogeny. We evaluate geographic structure by using 16 distinguishing binary markers in 1,631 hg N Y chromosomes from a collection of 6,521 samples from 56 populations. The more southerly distributed sub-clade N4 emerged before N2a1 and N3, found mostly in the north, but the latter two display more elaborate branching patterns, indicative of regional contrasts in recent expansions. In particular, a number of prominent and well-defined clades with common N3a3'6 ancestry occur in regionally dissimilar northern Eurasian populations, indicating almost simultaneous regional diversification and expansion within the last 5,000 years. This patrilineal genetic affinity is decoupled from the associated higher degree of language diversity.

SummaryInherited optic neuropathies are a heterogeneous group of disorders characterized by mild to severe visual loss, colour vision deficit, central or paracentral visual field defects and optic disc pallor. Optic atrophies can be classified into isolated or non-syndromic and syndromic forms. While multiple modes of inheritance have been reported, autosomal dominant optic atrophy and mitochondrial inherited Leber's hereditary optic neuropathy are the most common forms. Optic atrophy type 1, caused by mutations in theOPA1gene is believed to be the most common hereditary optic neuropathy, and most patients inherit a mutation from an affected parent. In this study we used whole-exome sequencing to investigate the genetic aetiology in a patient affected with isolated optic atrophy. Since the proband was the only affected individual in his extended family, and was a product of consanguineous marriage, homozygosity mapping followed by whole-exome sequencing were pursued. Exome results identified a novelde novo OPA1mutation in the proband. We conclude, that thoughde novo OPA1mutations are uncommon, testing of common optic atrophy-associated genes such as mitochondrial mutations andOPA1gene sequencing should be performed first in single individuals presenting with optic neuropathy, even when dominant inheritance is not apparent.

Background: Susceptibility to end-stage kidney disease (ESKD) among HIV-infected Americans of African ancestral heritage has been attributed to APOL1 genetic variation. We determined the frequency of the APOL1 G1 and G2 risk variants together with the prevalence of HIV-associated nephropathy (HIVAN) among individuals of Ethiopian ancestry to determine whether the kidney disease genetic risk is PanAfrican or restricted to West Africa, and can explain the previously reported low risk of HIVAN among Ethiopians. Methods: We studied a cohort of 338 HIV-infected individuals of Ethiopian ancestry treated in one Israeli and one Ethiopian center. We sought clinical evidence for HIVAN (serum creatinine >1.4 mg/dl or proteinuria >30 mg/dl in a spot urine sample). Genetic analyses included the genotyping of the APOL1 G1 and G2 variants, and a panel of 33 genomic ancestry-informative markers. Statistical analysis compared clinical and genetic indices for HIV-infected individuals of Ethiopian ancestry and overall Ethiopians to those reported for HIV-infected African-Americans, overall African-Americans, West Africans and non-Africans. Findings: Three (0.8%) of 338 HIV-infected patients of Ethiopian ancestry showed clinical criteria compatible with renal impairment. Two of these 3 patients also have severe poorly controlled diabetes mellitus. The third nondiabetic patient underwent renal biopsy which ruled out HIVAN. This absence of clinically apparent HIVAN was significantly different from that reported for African-Americans. The APOL1 G1 and G2 risk variants were found, respectively, in 0 and 2 (heterozygote state) of the 338 HIV-infected individuals. Global ancestry and the frequencies of the APOL1 G1 and G2 variants are not statistically different from their frequencies in the general Ethiopian population, but are significantly and dramatically lower than those observed among HIV-infected African-Americans, African-Americans and West Africans. Interpretation: The coinciding absence of HIVAN and the APOL1 risk variants among HIV-infected individuals of Ethiopian ancestry support a Western rather than Pan-African ancestry risk for ESKD, and can readily explain the lack of HIVAN among individuals of Ethiopian ancestry.

MYH9 has been proposed as a major genetic risk locus for a spectrum of nondiabetic end stage kidney disease (ESKD). We use recently released sequences from the 1000 Genomes Project to identify two western African-specific missense mutations (S342G and I384M) in the neighboring APOL1 gene, and demonstrate that these are more strongly associated with ESKD than previously reported MYH9 variants. The APOL1 gene product, apolipoprotein L-1, has been studied for its roles in trypanosomal lysis, autophagic cell death, lipid metabolism, as well as vascular and other biological activities. We also show that the distribution of these newly identified APOL1 risk variants in African populations is consistent with the pattern of African ancestry ESKD risk previously attributed to MYH9. Mapping by admixture linkage disequilibrium (MALD) localized an interval on chromosome 22, in a region that includes the MYH9 gene, which was shown to contain African ancestry risk variants associated with certain forms of ESKD (Kao et al. 2008; Kopp et al. 2008). MYH9 encodes nonmuscle myosin heavy chain IIa, a major cytoskeletal nanomotor protein expressed in many cell types, including podocyte cells of the renal glomerulus. Moreover, 39 different coding region mutations in MYH9 have been identified in patients with a group of rare syndromes, collectively termed the Giant Platelet Syndromes, with clear autosomal dominant inheritance, and various clinical manifestations, sometimes also including glomerular pathology and chronic kidney disease (Kopp 2010; Sekine et al. 2010). Accordingly, MYH9 was further explored in these studies as the leading candidate gene responsible for the MALD signal. Dense mapping of MYH9 identified individual single nucleotide polymorphisms (SNPs) and sets of such SNPs grouped as haplotypes that were found to be highly associated with a large and important group of ESKD risk phenotypes, which as a consequence were designated as MYH9-associated nephropathies (Bostrom and Freedman 2010). These included HIV-associated nephropathy (HIVAN), primary nonmonogenic forms of focal segmental glomerulosclerosis, and hypertension affiliated chronic kidney disease not attributed to other etiologies (Bostrom and Freedman 2010). The MYH9 SNP and haplotype associations observed with these forms of ESKD yielded the largest odds ratios (OR) reported to date for the association of common variants with common disease risk (Winkler et al. 2010). Two specific MYH9 variants (rs5750250 of S-haplotype and rs11912763 of F-haplotype) were designated as most strongly predictive on the basis of Receiver Operating Characteristic analysis (Nelson et al. 2010). These MYH9 association studies were then also extended to earlier stage and related kidney disease phenotypes and to population groups with varying degrees of recent African ancestry admixture (Behar et al. 2010; Freedman et al. 2009a, b; Nelson et al. 2010), and led to the expectation of finding a functional African ancestry causative variant within MYH9. However, despite intensive efforts including re-sequencing of the MYH9 gene no suggested functional mutation has been identified (Nelson et al. 2010; Winkler et al. 2010). This led us to re-examine the interval surrounding MYH9 and to the detection of novel missense mutations with predicted functional effects in the neighboring APOL1 gene, which are significantly more associated with ESKD than all previously reported SNPs in MYH9. Electronic supplementary material The online version of this article (doi:10.1007/s00439-010-0861-0) contains supplementary material, which is available to authorized users.

Recent studies identified MYH9 as a major susceptibility gene for common forms of non-diabetic end-stage kidney disease (ESKD). A set of African ancestry DNA sequence variants comprising the E-1 haplotype, was significantly associated with ESKD. In order to determine whether African ancestry variants are also associated with disease susceptibility in admixed populations with differing genomic backgrounds, we genotyped a total of 1425 African and Hispanic American subjects comprising dialysis patients with diabetic and non-diabetic ESKD and controls, using 42 single nucleotide polymorphisms (SNPs) within the MYH9 gene and 40 genome-wide and 38 chromosome 22 ancestry informative markers. Following ancestry correction, logistic regression demonstrated that three of the E-1 SNPs are also associated with non-diabetic ESKD in the new sample sets of both African and Hispanic Americans, with a stronger association in Hispanic Americans. We also identified MYH9 SNPs that are even more powerfully associated with the disease phenotype than the E-1 SNPs. These newly associated SNPs, could be divided into those comprising a haplotype termed S-1 whose association was significant under a recessive or additive inheritance mode (rs5750248, OR 4.21, P < 0.01, Hispanic Americans, recessive), and those comprising a haplotype termed F-1 whose association was significant under a dominant or additive inheritance mode (rs11912763, OR 4.59, P < 0.01, Hispanic Americans, dominant). These findings strengthen the contention that a sequence variant of MYH9, common in populations with varying degrees of African ancestry admixture, and in strong linkage disequilibrium with the associated SNPs and haplotypes reported herein, strongly predisposes to non-diabetic ESKD.

It has been known for over a decade that a majority of men who self report as members of the Jewish priesthood (Cohanim) carry a characteristic Y chromosome haplotype termed the Cohen Modal Haplotype (CMH). The CMH has since been used to trace putative Jewish ancestral origins of various populations. However, the limited number of binary and STR Y chromosome markers used previously did not provide the phylogenetic resolution needed to infer the number of independent paternal lineages that are encompassed within the Cohanim or their coalescence times. Accordingly, we have genotyped 75 binary markers and 12 Y-STRs in a sample of 215 Cohanim from diverse Jewish communities, 1,575 Jewish men from across the range of the Jewish Diaspora, and 2,099 non-Jewish men from the Near East, Europe, Central Asia, and India. While Cohanim from diverse backgrounds carry a total of 21 Y chromosome haplogroups, 5 haplogroups account for 79.5% of Cohanim Y chromosomes. The most frequent Cohanim lineage (46.1%) is marked by the recently reported P58 T->C mutation, which is prevalent in the Near East. Based on genotypes at 12 Y-STRs, we identify an extended CMH on the J-P58* background that predominates in both Ashkenazi and non-Ashkenazi Cohanim and is remarkably absent in non-Jews. The estimated divergence time of this lineage based on 17 STRs is 3,190 ± 1,090 years. Notably, the second most frequent Cohanim lineage (J-M410*, 14.4%) contains an extended modal haplotype that is also limited to Ashkenazi and non-Ashkenazi Cohanim and is estimated to be 4.2 ± 1.3 ky old. These results support the hypothesis of a common origin of the CMH in the Near East well before the dispersion of the Jewish people into separate communities, and indicate that the majority of contemporary Jewish priests descend from a limited number of paternal lineages. Electronic supplementary material The online version of this article (doi:10.1007/s00439-009-0727-5) contains supplementary material, which is available to authorized users.

It is commonly thought that human genetic diversity in non-African populations was primarily shaped by a recent out-of-Africa dispersal. Here we present a large geographical Y chromosome study using 459 high coverage sequences, including 302 newly reported here. We date the Y chromosomal Most Recent Common Ancestor (MRCA) in Africa at 254 (95% CI 192- 307) kya and differentiation of African and non-African lineages 52-121 kya. The age estimates for major non-African founder haplogroups cluster closely in a narrow time interval at 47-52 kya, consistent with a rapid initial colonization model of Eurasia and Oceania after the out-of-Africa bottleneck. We find that the highest basal Y chromosome diversity outside Africa has been preserved in South and Southeast Asians while extant Y chromosome diversity in Europe and the Near East stems from a small number of mid-Holocene founders. In contrast to demographic reconstructions based on mtDNA, we infer a second strong bottleneck, followed by a fast recovery in Old World populations dating to the last 10 ky. We hypothesize that this bottleneck is caused by cultural changes affecting variance of reproductive success among males.