Per Sjödin

Genomic Variation in Seven Khoe-San Groups Reveals Adaptation and Complex African History

African Origins Humans originated in Africa and then spread across the globe. The high genetic diversity found in sub-Saharan Africa is consistent with this view, but the relationships among and within African populations have been less well explored. Schlebusch et al. (p. 374, published online 20 September) genotyped 220 individuals from 11 populations representing groups from Southern Africa to determine their relationships and history. The data suggest that modern-day human populations arose from a complex blend of mixing between groups and genetic stratification. Cutting-edge genomic approaches test hypotheses about the roots of human history in southern African indigenous populations. The history of click-speaking Khoe-San, and African populations in general, remains poorly understood. We genotyped ∼2.3 million single-nucleotide polymorphisms in 220 southern Africans and found that the Khoe-San diverged from other populations ≥100,000 years ago, but population structure within the Khoe-San dated back to about 35,000 years ago. Genetic variation in various sub-Saharan populations did not localize the origin of modern humans to a single geographic region within Africa; instead, it indicated a history of admixture and stratification. We found evidence of adaptation targeting muscle function and immune response; potential adaptive introgression of protection from ultraviolet light; and selection predating modern human diversification, involving skeletal and neurological development. These new findings illustrate the importance of African genomic diversity in understanding human evolutionary history.

Joint analysis of demography and selection in population genetics : where do we stand and where could we go?

Teasing apart the effects of selection and demography on genetic polymorphism remains one of the major challenges in the analysis of population genomic data. The traditional approach has been to assume that demography would leave a genome‐wide signature, whereas the effect of selection would be local. In the light of recent genomic surveys of sequence polymorphism, several authors have argued that this approach is questionable based on the evidence of the pervasive role of positive selection and that new approaches are needed. In the first part of this review, we give a few empirical and theoretical examples illustrating the difficulty in teasing apart the effects of selection and demography on genomic polymorphism patterns. In the second part, we review recent efforts to detect recent positive selection. Most available methods still rely on an a priori classification of sites in the genome but there are many promising new approaches. These new methods make use of the latest developments in statistics, explore aspects of the data that had been neglected hitherto or take advantage of the emerging population genomic data. A current and promising approach is based on first estimating demographic and genetic parameters, using, e.g., a likelihood or approximate Bayesian computation framework, focusing on extreme outlier regions, and then using an independent method to confirm these. Finally, especially for species where evidence of natural selection has been limited, more experimental and versatile approaches that contrast populations under varied environmental constraints might be more successful compared with species‐wide genome scans in search of specific signatures.

Southern African ancient genomes estimate modern human divergence to 350,000 to 260,000 years ago

Ancient DNA pushes human emergence back Anatomically modern humans evolved in Africa, but pinpointing when has been difficult. Schlebusch et al. sequenced three ancient African genomes from the Stone Age, about 2000 years old, and four from the Iron Age, 300 to 500 years old. One of the oldest samples, sequenced to 13× coverage, appears most closely to resemble individuals from the present-day San population. However, this individual seems to have lacked genetic contributions from other modern African populations, including pastoralists and farmers, which were observed in modern San individuals. Thus, the earliest divergence between human populations may have occurred 350,000 to 260,000 years ago. Science, this issue p. 652 Ancient African genomes push back the timing of the split between human populations. Southern Africa is consistently placed as a potential region for the evolution of Homo sapiens. We present genome sequences, up to 13x coverage, from seven ancient individuals from KwaZulu-Natal, South Africa. The remains of three Stone Age hunter-gatherers (about 2000 years old) were genetically similar to current-day southern San groups, and those of four Iron Age farmers (300 to 500 years old) were genetically similar to present-day Bantu-language speakers. We estimate that all modern-day Khoe-San groups have been influenced by 9 to 30% genetic admixture from East Africans/Eurasians. Using traditional and new approaches, we estimate the first modern human population divergence time to between 350,000 and 260,000 years ago. This estimate increases the deepest divergence among modern humans, coinciding with anatomical developments of archaic humans into modern humans, as represented in the local fossil record.

Resequencing data provide no evidence for a human bottleneck in Africa during the penultimate glacial period

Based on the accumulation of genetic, climatic, and fossil evidence, a central theory in paleoanthropology stipulates that a demographic bottleneck coincided with the origin of our species Homo Sapiens. This theory proposes that anatomically modern humans--which were only present in Africa at the time--experienced a drastic bottleneck during the penultimate glacial age (130-190 kya) when a cold and dry climate prevailed. Two scenarios have been proposed to describe the bottleneck, which involve either a fragmentation of the range occupied by humans or the survival of one small group of humans. Here, we analyze DNA sequence data from 61 nuclear loci sequenced in three African populations using Approximate Bayesian Computation and numerical simulations. In contrast to the bottleneck theory, we show that a simple model without any bottleneck during the penultimate ice age has the greatest statistical support compared with bottleneck models. Although the proposed bottleneck is ancient, occurring at least 130 kya, we can discard the possibility that it did not leave detectable footprints in the DNA sequence data except if the bottleneck involves a less than a 3-fold reduction in population size. Finally, we confirm that a simple model without a bottleneck is able to reproduce the main features of the observed patterns of genetic variation. We conclude that models of Pleistocene refugium for modern human origins now require substantial revision.

Ancient mitochondrial DNA from the northern fringe of the Neolithic farming expansion in Europe sheds light on the dispersion process

The European Neolithization process started around 12 000 years ago in the Near East. The introduction of agriculture spread north and west throughout Europe and a key question has been if this was brought about by migrating individuals, by an exchange of ideas or a by a mixture of these. The earliest farming evidence in Scandinavia is found within the Funnel Beaker Culture complex (Trichterbecherkultur, TRB) which represents the northernmost extension of Neolithic farmers in Europe. The TRB coexisted for almost a millennium with hunter–gatherers of the Pitted Ware Cultural complex (PWC). If migration was a substantial part of the Neolithization, even the northerly TRB community would display a closer genetic affinity to other farmer populations than to hunter–gatherer populations. We deep-sequenced the mitochondrial hypervariable region 1 from seven farmers (six TRB and one Battle Axe complex, BAC) and 13 hunter–gatherers (PWC) and authenticated the sequences using postmortem DNA damage patterns. A comparison with 124 previously published sequences from prehistoric Europe shows that the TRB individuals share a close affinity to Central European farmer populations, and that they are distinct from hunter–gatherer groups, including the geographically close and partially contemporary PWC that show a close affinity to the European Mesolithic hunter–gatherers.

Investigating Population History Using Temporal Genetic Differentiation

The rapid advance of sequencing technology, coupled with improvements in molecular methods for obtaining genetic data from ancient sources, holds the promise of producing a wealth of genomic data from time-separated individuals. However, the population-genetic properties of time-structured samples have not been extensively explored. Here, we consider the implications of temporal sampling for analyses of genetic differentiation and use a temporal coalescent framework to show that complex historical events such as size reductions, population replacements, and transient genetic barriers between populations leave a footprint of genetic differentiation that can be traced through history using temporal samples. Our results emphasize explicit consideration of the temporal structure when making inferences and indicate that genomic data from ancient individuals will greatly increase our ability to reconstruct population history.

Anisotropic isolation by distance: the main orientations of human genetic differentiation

Genetic differentiation among human populations is greatly influenced by geography due to the accumulation of local allele frequency differences. However, little is known about the possibly different increment of genetic differentiation along the different geographical axes (north–south, east–west, etc.). Here, we provide new methods to examine the asymmetrical patterns of genetic differentiation. We analyzed genome-wide polymorphism data from populations in Africa (n = 29), Asia (n = 26), America (n = 9), and Europe (n = 38), and we found that the major orientations of genetic differentiation are north–south in Europe and Africa, and east–west in Asia, but no preferential orientation was found in the Americas. Additionally, we showed that the localization of the individual geographic origins based on single nucleotide polymorphism data was not equally precise along all orientations. Confirming our findings, we obtained that, in each continent, the orientation along which the precision is maximal corresponds to the orientation of maximum differentiation. Our results have implications for interpreting human genetic variation in terms of isolation by distance and spatial range expansion processes. In Europe, for instance, the precise northnorthwest–southsoutheast axis of main European differentiation cannot be explained by a simple Neolithic demic diffusion model without admixture with the local populations because in that case the orientation of greatest differentiation should be perpendicular to the direction of expansion. In addition to humans, anisotropic analyses can guide the description of genetic differentiation for other organisms and provide information on expansions of invasive species or the processes of plant dispersal.

Stronger signal of recent selection for lactase persistence in Maasai than in Europeans

Continued ability to digest lactose after weaning provides a possible selective advantage to individuals who have access to milk as a food source. The lactase persistence (LP) phenotype exists at varying frequencies in different populations and SNPs that modulate the regulation of the LCT gene have been identified in many of these populations. Very strong positive selection for LP has been illustrated for a single SNP (rs4988235) in northwestern European populations, which has become a textbook example of the effect of recent selective sweeps on genetic variation and linkage disequilibrium. In this study, we employed two different methods to detect signatures of positive selection in an East African pastoralist population in the HapMap collection, the Maasai from Kenya, and compared results with other HapMap populations. We found that signatures of recent selection coinciding with the LCT gene are the strongest across the genome in the Maasai population. Furthermore, the genome-wide signal of recent positive selection on haplotypic variation and population differentiation around the LCT gene is greater in the Maasai than in the CEU population (northwestern European descent), possibly due to stronger selection pressure, but it could also be an indication of more recent selection in Maasai compared with the Central European group or more efficient selection in the Maasai due to less genetic drift for their larger effective population size. This signal of recent selection is driven by a putative East African LP haplotype that is different from the haplotype that contributes to the LP phenotype in northwestern Europe.

Insertion and deletion processes in recent human history.

Background Although insertions and deletions (indels) account for a sizable portion of genetic changes within and among species, they have received little attention because they are difficult to type, are alignment dependent and their underlying mutational process is poorly understood. A fundamental question in this respect is whether insertions and deletions are governed by similar or different processes and, if so, what these differences are. Methodology/Principal Findings We use published resequencing data from Seattle SNPs and NIEHS human polymorphism databases to construct a genomewide data set of short polymorphic insertions and deletions in the human genome (n = 6228). We contrast these patterns of polymorphism with insertions and deletions fixed in the same regions since the divergence of human and chimpanzee (n = 10546). The macaque genome is used to resolve all indels into insertions and deletions. We find that the ratio of deletions to insertions is greater within humans than between human and chimpanzee. Deletions segregate at lower frequency in humans, providing evidence for deletions being under stronger purifying selection than insertions. The insertion and deletion rates correlate with several genomic features and we find evidence that both insertions and deletions are associated with point mutations. Finally, we find no evidence for a direct effect of the local recombination rate on the insertion and deletion rate. Conclusions/Significance Our data strongly suggest that deletions are more deleterious than insertions but that insertions and deletions are otherwise generally governed by the same genomic factors.

Population genetic nature of copy number variation.

Copy number variation has recently received considerable attention, and copy number variants (CNVs) have been shown to be both common in mammalian genomes and important for understanding genetic and phenotypic variation. As empirical knowledge and detection methods are quickly advancing, evolutionary theories about CNVs are rapidly updated and often revised. Here, we review recent progress on understanding CNVs, and we discuss some key issues for future research. In essence, we discuss four major forces in population genetics, recombination, mutation, selection, and demography, in relation to CNVs.