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A unique resource of longitudinal childhood height data available in Finnish population cohorts was used to study the largely unknown genetic underpinnings of height growth. The partially correlated variants at LIN28B which influence the entire period of postnatal growth implied a critical role for LIN28B in the regulation of human growth.

Structural variations of DNA greater than 1 kilobase in size account for most bases that vary among human genomes, but are still relatively under-ascertained. Here we use tiling oligonucleotide microarrays, comprising 42 million probes, to generate a comprehensive map of 11,700 copy number variations (CNVs) greater than 443 base pairs, of which most (8,599) have been validated independently. For 4,978 of these CNVs, we generated reference genotypes from 450 individuals of European, African or East Asian ancestry. The predominant mutational mechanisms differ among CNV size classes. Retrotransposition has duplicated and inserted some coding and non-coding DNA segments randomly around the genome. Furthermore, by correlation with known trait-associated single nucleotide polymorphisms (SNPs), we identified 30 loci with CNVs that are candidates for influencing disease susceptibility. Despite this, having assessed the completeness of our map and the patterns of linkage disequilibrium between CNVs and SNPs, we conclude that, for complex traits, the heritability void left by genome-wide association studies will not be accounted for by common CNVs., Genomes vary from one another in multifarious ways, and the totality of this genetic variation underpins the heritability of human traits. Over the past two years, the human reference sequence [...]

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.

A large-scale genome-wide survey of the nonsense SNPs is carried out to examine the prevalence and the various evolutionary forces acting on them in the human genome. These nonsense SNPs are proved to be slightly disadvantageous over the evolutionary timescales.

The mitochondrial DNA hypervariable segment I (HVS-I) is widely used in studies of human evolutionary genetics, and therefore accurate estimates of mutation rates among nucleotide sites in this region are essential. We have developed a novel maximum-likelihood methodology for estimating site-specific mutation rates from partial phylogenetic information, such as haplogroup association. The resulting estimation problem is a generalized linear model, with a nonstandard link function. We develop inference and bias correction tools for our estimates and a hypothesis-testing approach for site independence. We demonstrate our methodology using 16,609 HVS-I samples from the Genographic Project. Our results suggest that mutation rates among nucleotide sites in HVS-I are highly variable. The 16,400-16,500 region exhibits significantly lower rates compared to other regions, suggesting potential functional constraints. Several loci identified in the literature as possible termination-associated sequences (TAS) do not yield statistically slower rates than the rest of HVS-I, casting doubt on their functional importance. Our tests do not reject the null hypothesis of independent mutation rates among nucleotide sites, supporting the use of site-independence assumption for analyzing HVS-I. Potential extensions of our methodology include its application to estimation of mutation rates in other genetic regions, like Y chromosome short tandem repeats.

Several technical analyses are conducted to explain the biological significance and the adaptative evolution of the UGT2B17 copy-number variation (CNV) in humans, which varies from zero to two per individual. The observed diversity in the observed CNV is shown to be low in East Asia.

A matrilineal tree is developed and used to study the diversity and the structure of the mitochondrial DNA phylogeny at dawn of Homo sapiens. The early settlement of humans in Africa was shown to be matrilineally structured with small and separately evolving isolated populations.

The influence of various historical events and religion on the observed Y-chromosomal diversity and other current patrilienal variations are explained. The Islamic and Crusader activities in the country were found to be the reason behind the invasion of the Arabian and European lineages among its people.

Author(s): Richard Redon [1]; Shumpei Ishikawa [2, 3]; Karen R. Fitch [4]; Lars Feuk [5, 6]; George H. Perry [7]; T. Daniel Andrews [1]; Heike Fiegler [1]; Michael H. Shapero [...]

ABSTRACT Malaria is perhaps the most important parasitic infection and strongest known force for selection in the recent evolutionary history of the human genome. Genetically-determined resistance to malaria has been [...]

Copy number variation is surprisingly common among humans and can be involved in phenotypic diversity and variable susceptibility to complex diseases, but little is known of the extent of copy number variation in nonhuman primates. We have used two array-based comparative genomic hybridization platforms to identify a total of 355 copy number variants (CNVs) in the genomes of 20 wild-born chimpanzees (Pan troglodytes) and have compared the identified chimpanzee CNVs to known human CNVs from previous studies. Many CNVs were observed in the corresponding regions in both chimpanzees and humans; especially those CNVs of higher frequency. Strikingly, these loci are enriched 20-fold for ancestral segmental duplications, which may facilitate CNV formation through nonallelic homologous recombination mechanisms. Therefore, some of these regions may be unstable 'hotspots' for the genesis of copy number variation, with recurrent duplications and deletions occurring across and within species. chimpanzee genome | human evolution | structural genomic variation

The human population has increased greatly in size in the last 100,000 years, but the initial stimuli to growth, the times when expansion started, and their variation between different parts of the world are poorly understood. We have investigated male demography in East Asia, applying a Bayesian full-likelihood analysis to data from 988 men representing 27 populations from China, Mongolia, Korea, and Japan typed with 45 binary and 16 STR markers from the Y chromosome. According to our analysis, the northern populations examined all started to expand in number between 34 (18-68) and 22 (12-39) thousand years ago (KYA), before the last glacial maximum at 21-18 KYA, while the southern populations all started to expand between 18 (6-47) and 12 (1-45) KYA, but then grew faster. We suggest that the northern populations expanded earlier because they could exploit the abundant megafauna of the 'Mammoth Steppe,' while the southern populations could increase in number only when a warmer and more stable climate led to more plentiful plant resources such as tubers.

Diverse evolutionary solutions to centromere structure are discussed in this minireview article which focuses on the emerging molecular view of the diversity and the ways in which it contributes to the view of the function of centromeres. Topics include Arabidopsis centromeres, centromeric protein conservation and variation, and reasons for the diversity. Centromeres are required for accurate transmission of chromosomes in eukaryotes.

A fully functional human neocentromere has been transmitted through three generations. Neocentromeres can be normally transmitted at meiosis. An unusual Y chromosome with a primary constriction inside the long-arm heterochromatin was discovered in amniocytes of a woman aged 38. Since it was also found in her husband and brother-in-law, it was present in the father. The Y chromosome seems to have been deleted for part of the alphoid DNA, likely silencing the normal centromere. Neocentromere activation might have taken place first and brought on inactivation of the normal centromere through partial deletion.

Y chromosomal DNA polymorphisms have been used to study Pleistocene migrations to the American continent. In a sample of 306 men from all over the world, 32 haplotypes were established with the variations from 30 distinct polymorphic sites. The major Y haplotype in most Native Americans was followed back to recent ancestors common with Siberians, the Altaians and Kets from the Altai Mountains and the Yenissey River Basin, respectively, and then back to the next common ancestor. That one gave rise to Caucasoid Y chromosomes, likely from central Eurasia. The study indicates a mainly central Siberian origin for Native American paternal lineages for those who might have migrated to the Americas in the Upper Pleistocene.

Author(s): Luca Pagani (corresponding author) [1, 2, 3]; Daniel John Lawson [4]; Evelyn Jagoda [2, 5]; Alexander Mrseburg [2]; Anders Eriksson [6, 7]; Mario Mitt [8, 9]; Florian Clemente [2, [...]

The population history of Aboriginal Australians remains largely uncharacterized. Here we generate high-coverage genomes for 83 Aboriginal Australians (speakers of PamaNyungan languages) and 25 Papuans from the New Guinea Highlands. We find that Papuan and Aboriginal Australian ancestors diversified 2540 thousand years ago (kya), suggesting pre-Holocene population structure in the ancient continent of Sahul (Australia, New Guinea and Tasmania). However, all of the studied Aboriginal Australians descend from a single founding population that differentiated 1032 kya. We infer a population expansion in northeast Australia during the Holocene epoch (past 10,000 years) associated with limited gene flow from this region to the rest of Australia, consistent with the spread of the PamaNyungan languages. We estimate that Aboriginal Australians and Papuans diverged from Eurasians 5172 kya, following a single out-of-Africa dispersal, and subsequently admixed with archaic populations. Finally, we report evidence of selection in Aboriginal Australians potentially associated with living in the desert., Author(s): Anna-Sapfo Malaspinas [1, 2, 3]; Michael C. Westaway [4]; Craig Muller [1]; Vitor C. Sousa [2, 3]; Oscar Lao [5, 6]; Isabel Alves [2, 3, 7]; Anders Bergstrm [8]; [...]

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., Author(s): Swapan Mallick (corresponding author) [1, 2, 3]; Heng Li [2]; Mark Lipson [1]; Iain Mathieson [1]; Melissa Gymrek [2, 4, 5, 6]; Fernando Racimo [7]; Mengyao Zhao [1, 2, [...]

Common descent followed by molecular radiation accounts for most of the phenetic relationships among haplotypes in four Y-linked dinucleotide microsatellites among 908 men from Europe, northern Africa, and western Asia. Six large networks and two small ones emerged. The complete diversity within a sample can be partitioned using this technique. A low level of homoplasy is found among dinucleotide microsatellite haplotypes. Populations are highly structured in terms of Y-chromosomal network frequencies.

A Drosophila melanogasted yeast artificial chromosome library was constructed and probed with a DNA sequence from the minichromosome Dp(1;f)1187 derived from the X chromosome. The Dpf(1;f)1187 minichromosome contains G+C-rich tandemly repeated dodeca satellite sequences. The results showed that dodeca satellite sequences are present in heterochromatin of the centromeric region in D. melanogaster autosomes. Cross-hybridization experiments further demonstrated the presence of these sequences in widely divergent species such as Arabidopsis thaliana and humans.

Author(s): Aaron R. Everitt [1]; Simon Clare [1]; Thomas Pertel [2]; Sinu P. John [2]; Rachael S. Wash [1]; Sarah E. Smith [1]; Christopher R. Chin [2]; Eric M. Feeley [...]

A study was conducted to examine the variation in six binary polymorphisms and six microsatellite polymorphisms existing in the Mbenzele Pygmies of Central Africa Republic. The results reported a similarity between the Mbenzele Pygmies and the Baika Pygmies owing to a close geographical proximity between the two civilizations.

The frequency distributions of 4 highly polymorphic Y-chromosome-specific microsatellites (DYS19, DYS390, DYS391, and DYS392) were determined in 79 unrelated Australian Aboriginal males from the Northern Territory. These results are compared with those observed in worldwide populations at both the locus and the haplotype level. Common alleles in Aboriginals are DYS19*15 (49%), DYS19*14 (28%), DYS390*19 (39%), DYS390*24 (20%), DYS391*10 (72%), DYS392*11 (63%), and DYS392*13 (28%). No evidence of reduced gene diversity was observed for these Y-chromosome alleles. DYS390 exhibits the most complex arrangement, displaying a bimodal distribution composed of common alleles (*22-*26), and rare short alleles (*18-*20), with an intermediate allele (*21) being absent. DYS390*20, previously reported only in Papuans and Samoans, is observed for the first time in Aboriginals. Compared with a recent study of Aboriginals, our sample exhibits considerable diversity in the haplotypes associated with the rare DYS390*19 allele, indicating that this allele is of considerable antiquity, if it arose as a single deletion event. Combining all 4 Y-chromosome-linked microsatellites produced 41 unique haplotypes, which were linked using a median-joining network. This network shows that most (78%) of our Aboriginal haplotypes fall into 2 distinct clusters, which likely represent 2 separate lineages. Seven haplotypes are shared with haplotypes found in a recent study of Aboriginals, and 7 are shared with a Spanish population. The cluster of Aboriginal haplotypes associated with the short DYS390 alleles does not share any haplotypes with the Spanish, indicating that this cluster of haplotypes is unique to Australian Aboriginals. Limited data from 4 worldwide populations used to construct haplotypes based on 3 loci (DYSI9, DYS390, DYS392) show that only 4 of these haplotypes are seen in Australian Aboriginals. Shared haplotypes may be the result of admixture and/or recurrent mutation at these loci. Expanding the haplotype analysis to include biallelic markers on the Y chromosome will resolve this issue. KEY WORDS: Y CHROMOSOME, MICROSATELLITE, HAPLOTYPE, AUSTRALIAN ABORIGINAL, GENE DIVERSITY, NETWORK ANALYSIS, DYS19, DYS390, DYS391, DYS392, The nonrecombining portion of the human Y chromosome is inherited as a single unit, or haplotype, following a paternal line of transmission. Its genetic sequence therefore remains unchanged, except when [...]

We report the frequencies of a deletion polymorphism at the [Alpha]2 (1) collagen gene (COL1A2) and argue that this distribution has major implications for understanding the evolution of modern humans immediately after their exodus from sub-Saharan Africa as well as their subsequent spread to all continents. The high frequency of the deletion in non-African populations and its complete absence in sub-Saharan African groups suggest that the deletion event occurred just before or shortly after modern humans left Africa. The deletion probably arose shortly after the African exodus in a group whose descendants were among the ancestors of all contemporary populations, except for sub-Saharan Africans. This, of course, does not imply that there was a single migration out of Africa. The GM immunoglobulin haplotype GM*A,X G displays a similar distribution to that for the COL1A2 deletion, and these 2 polymorphisms suggest that the exodus from Africa may not have been a rapid dispersion to all other regions of the world. Instead, it may have involved a period of time for the savanna-derived gene pool to adapt to novel selective agents, such as bacteria, viruses, and/or environmental xenobiotics found in both animal and plant foods in their new environment. In this context these polymorphisms are indicators of the evolution that occurred before the diaspora of these populations to the current distribution of modern peoples. KEY WORDS: COL1A2 DELETION POLYMORPHISM, EVOLUTION, ORIGINS OF MODERN HUMANS, OUT OF AFRICA HYPOTHESIS, GM HAPLOTYPE, RECURRENT MUTATION, In recent years DNA polymorphisms have been used to reconstruct hominid phylogeny. In particular, studies of mtDNA (Vigilant et al. 1991; Stoneking and Soodyall 1996) and closely linked polymorphic loci [...]