Antti Sajantila

Correlation between Genetic and Geographic Structure in Europe

Understanding the genetic structure of the European population is important, not only from a historical perspective, but also for the appropriate design and interpretation of genetic epidemiological studies. Previous population genetic analyses with autosomal markers in Europe either had a wide geographic but narrow genomic coverage [1, 2], or vice versa [3-6]. We therefore investigated Affymetrix GeneChip 500K genotype data from 2,514 individuals belonging to 23 different subpopulations, widely spread over Europe. Although we found only a low level of genetic differentiation between subpopulations, the existing differences were characterized by a strong continent-wide correlation between geographic and genetic distance. Furthermore, mean heterozygosity was larger, and mean linkage disequilibrium smaller, in southern as compared to northern Europe. Both parameters clearly showed a clinal distribution that provided evidence for a spatial continuity of genetic diversity in Europe. Our comprehensive genetic data are thus compatible with expectations based upon European population history, including the hypotheses of a south-north expansion and/or a larger effective population size in southern than in northern Europe. By including the widely used CEPH from Utah (CEU) samples into our analysis, we could show that these individuals represent northern and western Europeans reasonably well, thereby confirming their assumed regional ancestry.

Characteristics and frequency of germline mutations at microsatellite loci from the human Y chromosome, as revealed by direct observation in father/son pairs.

A number of applications of analysis of human Y-chromosome microsatellite loci to human evolution and forensic science require reliable estimates of the mutation rate and knowledge of the mutational mechanism. We therefore screened a total of 4,999 meioses from father/son pairs with confirmed paternity (probability >/=99. 9%) at 15 Y-chromosomal microsatellite loci and identified 14 mutations. The locus-specific mutation-rate estimates were 0-8. 58x10-3, and the average mutation rate estimates were 3.17x10-3 (95% confidence interval [CI] 1.89-4.94x10-3) across 8 tetranucleotide microsatellites and 2.80x10-3 (95% CI 1.72-4.27x10-3) across all 15 Y-chromosomal microsatellites studied. Our data show a mutational bias toward length increase, on the basis of observation of more repeat gains than losses (10:4). The data are in almost complete agreement with the stepwise-mutation model, with 13 single-repeat changes and 1 double-repeat change. Sequence analysis revealed that all mutations occurred in uninterrupted homogenous arrays of >/=11 repeats. We conclude that mutation rates and characteristics of human Y-chromosomal microsatellites are consistent with those of autosomal microsatellites. This indicates that the general mutational mechanism of microsatellites is independent of recombination.

Evidence for variable selective pressures at MC1R.

It is widely assumed that genes that influence variation in skin and hair pigmentation are under selection. To date, the melanocortin 1 receptor (MC1R) is the only gene identified that explains substantial phenotypic variance in human pigmentation. Here we investigate MC1R polymorphism in several populations, for evidence of selection. We conclude that MC1R is under strong functional constraint in Africa, where any diversion from eumelanin production (black pigmentation) appears to be evolutionarily deleterious. Although many of the MC1R amino acid variants observed in non-African populations do affect MC1R function and contribute to high levels of MC1R diversity in Europeans, we found no evidence, in either the magnitude or the patterns of diversity, for its enhancement by selection; rather, our analyses show that levels of MC1R polymorphism simply reflect neutral expectations under relaxation of strong functional constraint outside Africa.

DNA Commission of the International Society of Forensic Genetics: recommendations on forensic analysis using Y- chromosome STRs

During the past few years the DNA commission of the International Society of Forensic Genetics has published a series of documents providing guidelines and recommendations concerning the application of DNA polymorphisms to the problems of human identification. This latest report addresses a relatively new area, namely Y-chromosome polymorphisms, with particular emphasis on short tandem repeats (STRs). This report addresses nomenclature, use of allelic ladders, population genetics and reporting methods.

The Simons Genome Diversity Project: 300 genomes from 142 diverse 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.

A Comprehensive Survey of Human Y-Chromosomal Microsatellites

We have screened the nearly complete DNA sequence of the human Y chromosome for microsatellites (short tandem repeats) that meet the criteria of having a repeat-unit size of > or = 3 and a repeat count of > or = 8 and thus are likely to be easy to genotype accurately and to be polymorphic. Candidate loci were tested in silico for novelty and for probable Y specificity, and then they were tested experimentally to identify Y-specific loci and to assess their polymorphism. This yielded 166 useful new Y-chromosomal microsatellites, 139 of which were polymorphic, in a sample of eight diverse Y chromosomes representing eight Y-SNP haplogroups. This large sample of microsatellites, together with 28 previously known markers analyzed here--all sharing a common evolutionary history--allowed us to investigate the factors influencing their variation. For simple microsatellites, the average repeat count accounted for the highest proportion of repeat variance (approximately 34%). For complex microsatellites, the largest proportion of the variance (again, approximately 34%) was explained by the average repeat count of the longest homogeneous array, which normally is variable. In these complex microsatellites, the additional repeats outside the longest homogeneous array significantly increased the variance, but this was lower than the variance of a simple microsatellite with the same total repeat count. As a result of this work, a large number of new, highly polymorphic Y-chromosomal microsatellites are now available for population-genetic, evolutionary, genealogical, and forensic investigations.

Alu insertion polymorphisms in NW Africa and the Iberian Peninsula: evidence for a strong genetic boundary through the Gibraltar Straits

Abstract. An analysis of 11 Alu insertion polymorphisms (ACE, TPA25, PV92, APO, FXIIIB, D1, A25, B65, HS2.43, HS3.23, and HS4.65) has been performed in several NW African (Northern, Western, and Southeastern Moroccans; Saharawi; Algerians; Tunisians) and Iberian (Basques, Catalans, and Andalusians) populations. Genetic distances and principal component analyses show a clear differentiation of NW African and Iberian groups of samples, suggesting a strong genetic barrier matching the geographical Mediterranean Sea barrier. The restriction to gene flow may be attributed to the navigational hazards across the Straits, but cultural factors must also have played a role. Some degree of gene flow from sub-Saharan Africa can be detected in the southern part of North Africa and in Saharawi and Southeastern Moroccans, as a result of a continuous gene flow across the Sahara desert that has created a south-north cline of sub-Saharan Africa influence in North Africa. Iberian samples show a substantial degree of homogeneity and fall within the cluster of European-based genetic diversity.

Global diversity, population stratification, and selection of human copy-number variation.

Duplications and deletions in the human genome Duplications and deletions can lead to variation in copy number for genes and genomic loci among humans. Such variants can reveal evolutionary patterns and have implications for human health. Sudmant et al. examined copy-number variation across 236 individual genomes from 125 human populations. Deletions were under more selection, whereas duplications showed more population-specific structure. Interestingly, Oceanic populations retain large duplications postulated to have originated in an ancient Denisovan lineage. Science, this issue 10.1126/science.aab3761 Copy-number variation reveals how selection affects the human genome across the globe. INTRODUCTION Most studies of human genetic variation have focused on single-nucleotide variants (SNVs). However, copy-number variants (CNVs) affect more base pairs of DNA among humans, and yet our understanding of CNV diversity among human populations is limited. RATIONALE We aimed to understand the pattern, selection, and diversity of copy-number variation by analyzing deeply sequenced genomes representing the diversity of all humans. We compared the selective constraints of deletions versus duplications to understand population stratification in the context of the ancestral human genome and to assess differences in CNV load between African and non-African populations. RESULTS We sequenced 236 individual genomes from 125 distinct human populations and identified 14,467 autosomal CNVs and 545 X-linked CNVs with a sequence read-depth approach. Deletions exhibit stronger selective pressure and are better phylogenetic markers of population relationships than duplication polymorphisms. We identified 1036 population-stratified copy-number–variable regions, 295 of which intersect coding regions and 199 of which exhibit extreme signatures of differentiation. Duplicated loci were 1.8-fold more likely to be stratified than deletions but were poorly correlated with flanking genetic diversity. Among these, we highlight a duplication polymorphism restricted to modern Oceanic populations yet also present in the genome of the archaic Denisova hominin. This 225–kilo–base pair (kbp) duplication includes two microRNA genes and is almost fixed among human Papuan-Bougainville genomes. The data allowed us to reconstruct the ancestral human genome and create a more accurate evolutionary framework for the gain and loss of sequences during human evolution. We identified 571 loci that segregate in the human population and another 2026 loci of fixed-copy 2 in all human genomes but absent from the reference genome. The total deletion and duplication load between African and non-African population groups showed no difference after we account for ancestral sequences missing from the human reference. However, we did observe that the relative number of base pairs affected by CNVs compared to single-nucleotide polymorphisms is higher among non-Africans than Africans. CONCLUSION Deletions, duplications, and CNVs have shaped, to different extents, the genetic diversity of human populations by the combined forces of mutation, selection, and demography. Figure Global human CNV diversity and archaic introgression of a chromosome 16 duplication. (Left) The geographic coordinates of populations sampled are indicated on a world map (colored dots). The pie charts show the continental population allele frequency of a single ~225-kbp duplication polymorphism found exclusively among Oceanic populations and an archaic Denisova. (Right) The ancestral structure of this duplication locus (1) and the Denisova duplication structure (2) are shown in relation to their position on chromosome 16. We estimate that the duplication emerged ~440 thousand years ago (ka) in the Denisova and then introgressed into ancestral Papuan populations ~40 ka. In order to explore the diversity and selective signatures of duplication and deletion human copy-number variants (CNVs), we sequenced 236 individuals from 125 distinct human populations. We observed that duplications exhibit fundamentally different population genetic and selective signatures than deletions and are more likely to be stratified between human populations. Through reconstruction of the ancestral human genome, we identify megabases of DNA lost in different human lineages and pinpoint large duplications that introgressed from the extinct Denisova lineage now found at high frequency exclusively in Oceanic populations. We find that the proportion of CNV base pairs to single-nucleotide–variant base pairs is greater among non-Africans than it is among African populations, but we conclude that this difference is likely due to unique aspects of non-African population history as opposed to differences in CNV load.

Pharmacogenetic variation at CYP2C9, CYP2C19, and CYP2D6 at global and microgeographic scales.

Objectives CYP2C9, CYP2C19, and CYP2D6 belong to a subfamily of cytochrome P450 (CYP) enzymes, associated mainly with the metabolism of exogenous compounds in the human body. The genes coding for these enzymes are highly polymorphic and thus of major pharmacogenetic importance. By systematically retrieving data from the literature and genotyping new population samples, we aimed at describing the worldwide distribution of genetic variation at these loci. We created a comprehensive resource of frequency data for the most important CYP2C9, CYP2C19, and CYP2D6 genetic variants in 129, 146, and 138 different population samples, respectively. Furthermore, we showed how demographic history can affect pharmacogenetic variation at a microgeographic scale by analyzing regional samples from Finland, which represents a well-known genetic isolate. Methods Data were obtained from the literature from 1991 to 2007 as well as by genotyping new population samples at four CYP2C9, two CYP2C19, and 12 CYP2D6 variable sites affecting enzymatic activity. Results and conclusion Our study shows that: (i) altered activity variants of CYP2C9, CYP2C19, and CYP2D6 occur globally in all geographic regions, reaching extremely high frequencies in some populations; (ii) each of the CYP genes studied shows a distinct geographic pattern of variation; (iii) population substructure can strongly affect the variation seen in pharmacogenetic loci; and (iv) several geographic regions of pharmacogenetic interest are still poorly characterized.

Evidence of still-ongoing convergence evolution of the lactase persistence T-13910 alleles in humans

A single-nucleotide variant, C/T(-13910), located 14 kb upstream of the lactase gene (LCT), has been shown to be completely correlated with lactase persistence (LP) in northern Europeans. Here, we analyzed the background of the alleles carrying the critical variant in 1,611 DNA samples from 37 populations. Our data show that the T(-13910) variant is found on two different, highly divergent haplotype backgrounds in the global populations. The first is the most common LP haplotype (LP H98) present in all populations analyzed, whereas the others (LP H8-H12), which originate from the same ancestral allelic haplotype, are found in geographically restricted populations living west of the Urals and north of the Caucasus. The global distribution pattern of LP T(-13910) H98 supports the Caucasian origin of this allele. Age estimates based on different mathematical models show that the common LP T(-13910) H98 allele (approximately 5,000-12,000 years old) is relatively older than the other geographically restricted LP alleles (approximately 1,400-3,000 years old). Our data about global allelic haplotypes of the lactose-tolerance variant imply that the T(-13910) allele has been independently introduced more than once and that there is a still-ongoing process of convergent evolution of the LP alleles in humans.