Differentiation between African populations is evidenced by the diversity of alleles and haplotypes of HLA class I loci

The allelic and haplotypic diversity of the HLA-A, HLA-B, and HLA-C loci was investigated in 852 subjects from five sub-Saharan populations from Kenya (Nandi and Luo), Mali (Dogon), Uganda, and Zambia. Distributions of genotypes at all loci and in all populations fit Hardy-Weinberg equilibrium expectations. There was not a single allele predominant at any of the loci in these populations, with the exception of A*3002 [allele frequency (AF) = 0.233] in Zambians and Cw*1601 (AF = 0.283) in Malians. This distribution was consistent with balancing selection for all class I loci in all populations, which was evidenced by the homozygosity F statistic that was less than that expected under neutrality. Only in the A locus in Zambians and the C locus in Malians, the AF distribution was very close to neutrality expectations. There were six instances in which there were significant deviations of allele distributions from neutrality in the direction of balancing selection. All allelic lineages from each of the class I loci were found in all the African populations. Several alleles of these loci have intermediate frequencies (AF = 0.020-0.150) and seem to appear only in the African populations. Most of these alleles are widely distributed in the African continent and their origin may predate the separation of linguistic groups. In contrast to native American and other populations, the African populations do not seem to show extensive allelic diversification within lineages, with the exception of the groups of alleles A*02, A*30, B*57, and B*58. The alleles of human leukocyte antigen (HLA)-B are in strong linkage disequilibrium (LD) with alleles of the C locus, and the sets of B/C haplotypes are found in several populations. The associations between A alleles with C-blocks are weaker, and only a few A/B/C haplotypes (A*0201-B*4501-Cw*1601; A*2301-B*1503-Cw*0202; A*7401-B* 1503-Cw*0202; A*2902-B*4201-Cw*1701; A*3001-B*4201-Cw*1701; and A*3601-B*5301-Cw*0401) are found in multiple populations with intermediate frequencies [haplotype frequency (HF) = 0.010-0.100]. The strength of the LD associations between alleles of HLA-A and HLA-B loci and those of HLA-B and HLA-C loci was on average of the same or higher magnitude as those observed in other non-African populations for the same pairs of loci. Comparison of the genetic distances measured by the distribution of alleles at the HLA class I loci in the sub-Saharan populations included in this and other studies indicate that the Luo population from western Kenya has the closest distance with virtually all sub-Saharan population so far studied for HLA-A, a finding consistent with the putative origin of modern humans in East Africa. In all African populations, the genetic distances between each other are greater than those observed between European populations. The remarkable current allelic and haplotypic diversity in the HLA system as well as their variable distribution in different sub-Saharan populations is probably the result of evolutionary forces and environments that have acted on each individual population or in their ancestors. In this regard, the genetic diversity of the HLA system in African populations poses practical challenges for the design of T-cell vaccines and for the transplantation medical community to find HLA-matched unrelated donors for patients in need of an allogeneic transplant.     

Genetic variation among world populations: inferences from 100 Alu insertion polymorphisms

We examine the distribution and structure of human genetic diversity for 710 individuals representing 31 populations from Africa, East Asia, Europe, and India using 100 Alu insertion polymorphisms from all 22 autosomes. Alu diversity is highest in Africans (0.349) and lowest in Europeans (0.297). Alu insertion frequency is lowest in Africans (0.463) and higher in Indians (0.544), E. Asians (0.557), and Europeans (0.559). Large genetic distances are observed among African populations and between African and non-African populations. The root of a neighbor-joining network is located closest to the African populations. These findings are consistent with an African origin of modern humans and with a bottleneck effect in the human populations that left Africa to colonize the rest of the world. Genetic distances among all pairs of populations show a significant product-moment correlation with geographic distances (r = 0.69, P < 0.00001). F(ST), the proportion of genetic diversity attributable to population subdivision is 0.141 for Africans/E. Asians/Europeans, 0.047 for E. Asians/Indians/Europeans, and 0.090 for all 31 populations. Resampling analyses show that approximately 50 Alu polymorphisms are sufficient to obtain accurate and reliable genetic distance estimates. These analyses also demonstrate that markers with higher F(ST) values have greater resolving power and produce more consistent genetic distance estimates.     

The place of the Basques in the European Y-chromosome diversity landscape

There is a trend to consider the gene pool of the Basques as a 'living fossil' of the earliest modern humans that colonized Europe. To investigate this assumption, we have typed 45 binary markers and five short tandem repeat loci of the Y chromosome in a set of 168 male Basques. Results on these combined haplotypes were analyzed in the context of matching data belonging to approximately 3000 individuals from over 20 European, Near East and North African populations, which were compiled from the literature. Our results place the low Y-chromosome diversity of Basques within the European diversity landscape. This low diversity seems to be the result of a lower effective population size maintained through generations. At least some lineages of Y chromosome in modern Basques originated and have been evolving since pre-Neolithic times. However, the strong genetic drift experienced by the Basques does not allow us to consider Basques either the only or the best representatives of the ancestral European gene pool. Contrary to previous suggestions, we do not observe any particular link between Basques and Celtic populations beyond that provided by the Paleolithic ancestry common to European populations, nor we find evidence supporting Basques as the focus of major population expansions.     

Mitochondrial and Y Chromosome Diversity in the English-Speaking Caribbean

The transatlantic slave trade lasted over three centuries and represents one of the largest forced migrations in human history. The biological repercussions are not well understood especially in African-Caribbean populations. This paper explores the effects of the forced migration, isolation, and admixture on genetic diversity using mitochondrial and Y chromosome markers for 501 individuals from Dominica, Grenada, Jamaica, St. Kitts, St. Lucia, St. Thomas, St. Vincent, and Trinidad. Genetic diversity and population genetic structure analyses of mitochondrial data and Y chromosome data indicate that there was no post-migration loss in genetic diversity in the African derived lineages. Genetic structure was observed between the islands for both genetic systems. This may be due to isolation, differences in the number and source of Africans imported, depopulation of indigenous populations, and/or differences in colonization history. Nearly 10% of the individuals belonged to a non-African mitochondrial haplogroup. In contrast, Y chromosome admixture estimates showed that there was nearly 30% European contribution to these Caribbean populations. This study sheds light on the history of Africans in the Americas as well as contributing to our understanding of the nature and extent of diversity within the African Diaspora.     

Alu Insertion Polymorphisms and Human Evolution: Evidence for a Larger Population Size in Africa

Alu insertion polymorphisms (polymorphisms consisting of the presence/absence of an Alu element at a particular chromosomal location) offer several advantages over other nuclear DNA polymorphisms for human evolution studies. First, they are typed by rapid, simple, PCR-based assays; second, they are stable polymorphisms—newly inserted Alu elements rarely undergo deletion; third, the presence of an Alu element represents identity by descent—the probability that different Alu elements would independently insert into the exact same chromosomal location is negligible; and fourth, the ancestral state is known with certainty to be the absence of an Alu element. We report here a study of 8 loci in 1500 individuals from 34 worldwide populations. African populations exhibit the most between-population differentiation, and the population tree is rooted in Africa; moreover, the estimated effective time of separation of African versus non-African populations is 137,000±15,000 years ago, in accordance with other genetic data. However, a principal coordinates analysis indicates that populations from Sahul (Australia and New Guinea) are nearly as close to the hypothetical ancestor as are African populations, suggesting that there was an early expansion of tropical populations of our species. An analysis of heterozygosity versus genetic distance suggests that African populations have had a larger effective population size than non-African populations. Overall, these results support the African origin of modern humans in that an earlier expansion of the ancestors of African populations is indicated.     

An Asian–Native American paternal lineage identified by RPS4Y resequencing and by microsatellite haplotyping

Human paternal population history was studied in 9 populations [three Native American, three Asian, two Caucasian and one African-derived sample(s)] using sequence and short tandem repeat haplotype diversity within the non-pseudoautosegmal region of the Y chromosome. Complete coding and additional flanking sequences (949 base pairs) of the RPS4Y locus were determined in 59 individuals from three of the populations, revealing a nucleotide diversity of 0.0147%, consistent with previous estimates from Y chromosome resequencing studies. One RPS4Y sequence variant, 711C>T, was polymorphic in Asian and Native American populations, but not in African and Caucasian population samples. The RPS4Y 711C>T variant, a second unique sequence variant at DYS287 and nine Y chromosome short tandem repeat (YSTR) loci were used to analyze the evolution of Y chromosome lineages. Three unambiguous lineages were defined in Asian, Native American and Jamaican populations using sequence variants at RPS4Y and DYS287 . These lineages were independently supported by the haplotypes defined solely by YSTR alleles, demonstrating the haplotypes constructed from YSTRs can evaluate population diversity, admixture and phylogeny.     

Recovering the geographic origin of early modern humans by realistic and spatially explicit simulations

Most genetic and archeological evidence argue in favor of a recent and unique origin of modern humans in sub-Saharan Africa, but no attempt has ever been made at quantifying the likelihood of this model, relative to alternative hypotheses of human evolution. In this paper, we investigate the possibility of using multilocus genetic data to correctly infer the geographic origin of humans, and to distinguish between a unique origin (UO) and a multiregional evolution (ME) model. We introduce here an approach based on realistic simulations of the genetic diversity expected after an expansion process of modern humans into the Old World from different possible areas and their comparison to observed data. We find that the geographic origin of the expansion can be correctly recovered provided that a large number of independent markers are used, and that precise information on past demography and potential places of origins is available. In that case, it is also possible to unambiguously distinguish between a unique origin and a multiregional model of human evolution. Application to a real human data set of 377 STR markers tested in 22 populations points toward a unique but surprising North African origin of modern humans. We show that this result could be due to ascertainment bias in favor of markers selected to be polymorphic in Europeans. A new estimation modeling this bias explicitly reveals that East Africa is the most likely place of origin for modern humans.     

Phylogeography of the Y‐chromosome haplogroup C in northern Eurasia

To reconstruct the phylogenetic structure of Y‐chromosome haplogroup (hg) C in populations of northern Eurasia, we have analyzed the diversity of microsatellite (STR) loci in a total sample of 413 males from 18 ethnic groups of Siberia, Eastern Asia and Eastern Europe. Analysis of SNP markers revealed that all Y‐chromosomes studied belong to hg C3 and its subhaplogroups C3c and C3d, although some populations (such as Mongols and Koryaks) demonstrate a relatively high input (more than 30%) of yet unidentified C3* haplotypes. Median joining network analysis of STR haplotypes demonstrates that Y‐chromosome gene pools of populations studied are characterized by the presence of DNA clusters originating from a limited number of frequent founder haplotypes. These are subhaplogroup C3d characteristic for Mongolic‐speaking populations, “star cluster” in C3* paragroup, and a set of DYS19 duplicated C3c Y‐chromosomes. All these DNA clusters show relatively recent coalescent times (less than 3000 years), so it is probable that founder effects, including social selection resulting in high male fertility associated with a limited number of paternal lineages, may explain the observed distribution of hg C3 lineages.     

Characterization of mtDNA variation in a cohort of South African paediatric patients with mitochondrial disease

Mitochondrial disease can be attributed to both mitochondrial and nuclear gene mutations. It has a heterogeneous clinical and biochemical profile, which is compounded by the diversity of the genetic background. Disease-based epidemiological information has expanded significantly in recent decades, but little information is known that clarifies the aetiology in African patients. The aim of this study was to investigate mitochondrial DNA variation and pathogenic mutations in the muscle of diagnosed paediatric patients from South Africa. A cohort of 71 South African paediatric patients was included and a high-throughput nucleotide sequencing approach was used to sequence full-length muscle mtDNA. The average coverage of the mtDNA genome was 81±26 per position. After assigning haplogroups, it was determined that although the nature of non-haplogroup-defining variants was similar in African and non-African haplogroup patients, the number of substitutions were significantly higher in African patients. We describe previously reported disease-associated and novel variants in this cohort. We observed a general lack of commonly reported syndrome-associated mutations, which supports clinical observations and confirms general observations in African patients when using single mutation screening strategies based on (predominantly non-African) mtDNA disease-based information. It is finally concluded that this first extensive report on muscle mtDNA sequences in African paediatric patients highlights the need for a full-length mtDNA sequencing strategy, which applies to all populations where specific mutations is not present. This, in addition to nuclear DNA gene mutation and pathogenicity evaluations, will be required to better unravel the aetiology of these disorders in African patients.     

Multilocus patterns of nucleotide variability and the demographic and selection history of Drosophila melanogaster populations

Uncertainty about the demographic history of populations can hamper genome-wide scans for selection based on population genetic models. To obtain a portrait of the effects of demographic history on genome variability patterns in Drosophila melanogaster populations, we surveyed noncoding DNA polymorphism at 10 X-linked loci in large samples from three African and two non-African populations. All five populations show significant departures from expectations under the standard neutral model. We detect weak but significant differentiation between East (Kenya and Zimbabwe) and West/Central sub-Saharan (Gabon) African populations. A skew toward high-frequency-derived polymorphisms, elevated levels of linkage disequilibrium (LD) and significant heterogeneity in levels of polymorphism and divergence in the Gabon sample suggest that this population is further from mutation-drift equilibrium than the two Eastern African populations. Both non-African populations harbor significantly higher levels of LD, a large excess of high-frequency-derived mutations and extreme heterogeneity among loci in levels of polymorphism and divergence. Rejections of the neutral model in D. melanogaster populations using these and similar features have been interpreted as evidence for an important role for natural selection in shaping genome variability patterns. Based on simulations, we conclude that simple bottleneck models are sufficient to account for most, if not all, polymorphism features of both African and non-African populations. In contrast, we show that a steady-state recurrent hitchhiking model fails to account for several aspects of the data. Demographic departures from equilibrium expectations in both ancestral and derived populations thus represent a serious challenge to detecting positive selection in genome-wide scans using current methodologies.     

Y-chromosome SNP haplotypes suggest evidence of gene flow among caste, tribe, and the migrant Siddi populations of Andhra Pradesh, South India

From observations of lack of haplotype sharing based on Y-chromosome specific short tandem repeat (STR) loci, previous reports suggested negligible gene flow among different geographic populations of India. Using Single Nucleotide Polymorphism (SNP) sites in combination with STRs, we observed evidence of haplotype sharing across caste-tribe boundaries in South India. We examined 27 SNPs in the non-recombining region of the Y chromosome to investigate gene flow in 204 individuals belonging to three caste groups (Vizag Brahmins, Peruru Brahmins, Kammas), three tribes (Bagata, Poroja, Valmiki) and an additional group (the Siddis) of African ancestry. Principal component and AMOVA analyses show that the between group component of variation is non-significant (P>0.05), while that among populations within the caste and tribal groups is significant (P<0.001). In particular, the Valmikis and Siddis are close to the caste groups. Of a total of 11 distinct SNP-haplotypes observed, the two tribal groups (Bagata and Poroja) lack the haplotypes H4, H4A, H5A and H16, which are seen in the caste groups. In contrast, all three tribal groups exhibit the Southeast Asian haplotype H11 that is absent in the caste populations. The presence of haplotypes H4, H5, H14, and H16 in the Siddis indicate that they have assimilated considerable non-African admixture. The evidence of haplotype sharing between castes and tribes is also found when the H14 lineage was further subdivided by five STR loci. We conclude that even though these SNP-based Y-haplotypes are able to distinguish the populations, gene flow in these South Indian populations is not as negligible as that inferred from other studies based on Y-specific short tandem repeat markers.     

人类Y染色体STR位点在群体遗传学中的应用

Y染色体STR位点在群体遗传学研究中是线粒体DNA的有益补充,是研究男性进化历史的绝好工具.本文介绍了Y-STR位点的遗传学特点以及多态性研究进展;总结了应用Y-STR位点进行群体遗传学研究的常用方法:直接比较法、分子变异分析构建系统树、分层聚类分析、主成分分析等;同时指出了应用Y-STR位点用于群体遗传学研究存在的问题和今后的发展方向.     

Dynamics of CAG repeat loci revealed by the analysis of their variability

In order to understand the dynamics of the expressed single tandem repeat trinucleotides (most of them involved in pathological expansion), the diversity in 10 different loci (SCA1, SCA2, SCA3, SCA6, SCA8, SCA12, DRPLA, HD, KCNN3, and NCOA3) was analyzed in four major human groups (Africans, Europeans, Indians, and East Asians). The present analysis intends to disentangle population-based from genetic-based factors having shaped STR (trinucleotide) variation and to recognize, for each locus, the specific rate and pattern of mutation (bias toward expansion or contraction, constraints on allele size), and the footprints of selection. Population differences account for a very small part of the total variation, but a clear footprint appears of population growth after a bottleneck in all non-African populations, giving support to the out-of-Africa model of modern humans. Most of the diversity is found among loci, and different dynamics are inferred for each of them. SCA2 and SCA3 follow an unrestricted stepwise mutation model, while the rest of loci are found under allele size constrictions and a bias to expansion (SCA1, SCA6, HD, and KCNN3), contraction (SCA12, DRPLA, and NCOA3), or unbiased (SCA8).     

Relationships between intrapopulational and interpopulational genetic diversity in man

The bottleneck effect (or extended period of reduced population size) is known to increase genetic distance (D) substantially, and this can be a serious factor that disturbs the phylogenetic relationships of populations inferred from genetic distance estimates. The bottleneck effect is also known to be a factor that disturbs the hierarchial relationships of the fixation indices (FST) or the coefficients of gene differentiation (GST) in subdivided populations. To examine the extent of the bottleneck effect on D and GST in human populations, the D and GST values were computed for various groups of populations from around the world, and their relationships with within-population heterozygosities were examined by using gene frequency data for protein and immunological loci. The results obtained indicate that the D value between a pair of populations is negatively correlated with the average within-population heterozygosity. This suggests that genetic distance estimates for small populations are seriously affected by the bottleneck effect, and that phylogenetic trees should be studied by taking into account this factor. The bottleneck effect on GST was also revealed from examination of the total gene diversity HT and its components, interpopulational genetic variation (DST) and intrapopulational genetic variation (HS). That is, a large value of GST in small populations was sometimes associated with the decrease of HS rather than the increase of DST. Generally speaking, however, GST was larger when geographically distant populations were considered than when closely located populations were considered. When there is any trace of bottleneck effects, phylogenetic trees should be constructed by a method in which the rate of evoluationary change is allowed to vary from branch to branch.     

Unique origin of Andaman Islanders: insight from autosomal loci

Our mtDNA and Y chromosome studies lead to the conclusion that the Andamanese “Negrito” mtDNA lineages have survived in the Andaman Islands in complete genetic isolation from other South and Southeast Asian populations since the initial settlement of the region by the out-of-Africa migration. In order to obtain a robust reconstruction of the evolutionary history of the Andamanese, we carried out a study on the three aboriginal populations, namely, the Great Andamanese, Onge and Nicobarese, using autosomal microsatellite markers. The range of alleles (7–31.2) observed in the studied population and heterozygosity values (0.392–0.857) indicate that the selected STR markers are highly polymorphic in all the three populations, and genetic variability within the populations is significantly high, with a mean gene diversity of 77%. The Andaman “Negrito” populations do not show particular affinities either with the African populations or with the Indian populations, confirming their unique origin. In contrast, Nicobarese show close affinities with the Southeast Asian populations, suggesting their recent entry in the Islands.     

The ‘extremely ancient' chromosome that isn't: a forensic bioinformatic investigation of Albert Perry's X-degenerate portion of the Y chromosome

Mendez and colleagues reported the identification of a Y chromosome haplotype (the A00 lineage) that lies at the basal position of the Y chromosome phylogenetic tree. Incorporating this haplotype, the authors estimated the time to the most recent common ancestor (TMRCA) for the Y tree to be 338 000 years ago (95% CI=237 000–581 000). Such an extraordinarily early estimate contradicts all previous estimates in the literature and is over a 100 000 years older than the earliest fossils of anatomically modern humans. This estimate raises two astonishing possibilities, either the novel Y chromosome was inherited after ancestral humans interbred with another species, or anatomically modern Homo sapiens emerged earlier than previously estimated and quickly became subdivided into genetically differentiated subpopulations. We demonstrate that the TMRCA estimate was reached through inadequate statistical and analytical methods, each of which contributed to its inflation. We show that the authors ignored previously inferred Y-specific rates of substitution, incorrectly derived the Y-specific substitution rate from autosomal mutation rates, and compared unequal lengths of the novel Y chromosome with the previously recognized basal lineage. Our analysis indicates that the A00 lineage was derived from all the other lineages 208 300 (95% CI=163 900–260 200) years ago.     

24个群体11个Y-STR基因座单倍型遗传关系的聚类分析

目的 选择具有高度遗传多态性与稳定性的11个Y-STR基因座,从父系遗传角度探讨24个群体的分子遗传学关系.方法 应用PowerPlex(R)Y System荧光标记复合扩增系统检测204名回族、280名锡伯族、203名满族、215名重庆土家族无关男性个体血样,用ABI310遗传分析仪进行基因分型,计算等位基因和单倍型频率,并结合已公开发表的国内外其他20个群体相同基因座的单倍型数据,计算各群体间的遗传距离Rst,进行聚类分析,并采用Neighbor-Joining法重建系统发生树.结果 不同群体特定Y-STR的单倍型频率和遗传距离存在差异;聚类分析与系统发生树结果一致,12个汉族群体主要分为南北两类,云南和四川汉族与北方汉族遗传距离较近(0.002 3、0.000 6);沈阳回族群体自成一类,其他少数民族彼此独立分支,其中朝鲜族与韩国、日本遗传距离较近(0.013 3、0.041 3).结论 24个群体之间存在一定的基因交流,个别少数民族相对独立;研究特定Y-STR单倍型数据的遗传距离对了解各群体的起源、迁移以及相互关系有重要的意义.     

24个群体11个Y-STR基因座单倍型遗传关系的聚类分析

目的 选择具有高度遗传多态性与稳定性的11个Y-STR基因座,从父系遗传角度探讨24个群体的分子遗传学关系.方法 应用PowerPlex(R)Y System荧光标记复合扩增系统检测204名回族、280名锡伯族、203名满族、215名重庆土家族无关男性个体血样,用ABI310遗传分析仪进行基因分型,计算等位基因和单倍型频率,并结合已公开发表的国内外其他20个群体相同基因座的单倍型数据,计算各群体间的遗传距离Rst,进行聚类分析,并采用Neighbor-Joining法重建系统发生树.结果 不同群体特定Y-STR的单倍型频率和遗传距离存在差异;聚类分析与系统发生树结果一致,12个汉族群体主要分为南北两类,云南和四川汉族与北方汉族遗传距离较近(0.002 3、0.000 6);沈阳回族群体自成一类,其他少数民族彼此独立分支,其中朝鲜族与韩国、日本遗传距离较近(0.013 3、0.041 3).结论 24个群体之间存在一定的基因交流,个别少数民族相对独立;研究特定Y-STR单倍型数据的遗传距离对了解各群体的起源、迁移以及相互关系有重要的意义.     

Searching for archaic contribution in Africa

Abstract

Context: Africa’s role in the narrative of human evolution is indisputably emphasised in the emergence of Homo sapiens. However, once humans dispersed beyond Africa, the history of those who stayed remains vastly under-studied, lacking the proper attention the birthplace of both modern and archaic humans deserves. The sequencing of Neanderthal and Denisovan genomes has elucidated evidence of admixture between archaic and modern humans outside of Africa, but has not aided efforts in answering whether archaic admixture happened within Africa.

Objectives: This article reviews the state of research for archaic introgression in African populations and discusses recent insights into this topic.

Methods: Gathering published sources and recently released preprints, this review reports on the different methods developed for detecting archaic introgression. Particularly it discusses how relevant these are when implemented on African populations and what findings these studies have shown so far.

Results: Methods for detecting archaic introgression have been predominantly developed and implemented on non-African populations. Recent preprints present new methods considering African populations. While a number of studies using these methods suggest archaic introgression in Africa, without an African archaic genome to validate these results, such findings remain as putative archaic introgression.

Conclusion: In light of the caveats with implementing current archaic introgression detection methods in Africa, we recommend future studies to concentrate on unravelling the complicated demographic history of Africa through means of ancient DNA where possible and through more focused efforts to sequence modern DNA from more representative populations across the African continent.