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The impact of whole-genome sequencing on the reconstruction of human population history

Key Points

  • Before the development of second-generation sequencing, the consensus opinion based on both fossil evidence and genetic evidence (which is based on single-locus and multilocus data) regarding human origins tended to favour a single recent African origin over a multiregional evolution model. The sequencing of the archaic Neanderthal and Denisovan genomes has shown that much more complex intermediate models are needed to explain the data.

  • The genome of an Australian Aborigine seems to provide evidence for two waves of migration through Asia shortly after anatomically modern humans (AMHs) left Africa ~60,000–50,000 years ago. However, recent estimates of the human mutation rate have raised the question of whether population divergence dates between Africans and non-Africans that are estimated from genetic data reflect the movement of people out of Africa or a much more complex demographic scenario that involves substantial ancient population structure and back migration.

  • Whole-genome sequencing (WGS) data from modern hunter-gatherers in Africa show that the click-speaking Khoe–Sans, followed by African Pygmies, are the most diverged AMH population alive today and that the Khoe–Sans maintain some genetic link with other click-speakers in Tanzania. However, robust inference of population history in Africa will require approaches that take into account 'ghost' archaic hominins from which ancient DNA is unlikely to be retrieved in the near future.

  • The geographical distribution of classical markers, non-recombining portions of the Y chromosome and mitochondrial DNA has resulted in substantial debate regarding the relative contributions of Paleolithic and Neolithic populations to the genetic ancestry of modern Europeans. Second-generation sequencing of ancient samples from these two prehistoric periods seems to suggest a major reshaping of European genetic diversity as part of the transition to a farming way of life.

  • WGS of ancient genomes is providing evidence that the prehistoric colonization of the Americas involved multiple waves of migrations over the Bering Strait and that the source populations are likely to derive from a relatively heterogeneous gene pool, which reflects periods of substantial demographic change in East Asia and Siberia since the Last Glacial Maximum.

  • Substantial efforts have been devoted to developing methods for inferring demographic history that can correct for, or are insensitive to, nucleotide calling errors that are produced during second-generation sequencing, especially when examining the allele frequency spectrum using low and medium coverage data sets. In addition, the sequentially Markovian coalescent model is providing the basis for many methods that are attempting to incorporate recombination into analytically novel methods, whereas third-generation sequencing technologies may provide extensive haplotype-phased data to fully exploit such approaches.

Abstract

Examining patterns of molecular genetic variation in both modern-day and ancient humans has proved to be a powerful approach to learn about our origins. Rapid advances in DNA sequencing technology have allowed us to characterize increasing amounts of genomic information. Although this clearly provides unprecedented power for inference, it also introduces more complexity into the way we use and interpret such data. Here, we review ongoing debates that have been influenced by improvements in our ability to sequence DNA and discuss some of the analytical challenges that need to be overcome in order to fully exploit the rich historical information that is contained in the entirety of the human genome.

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Figure 1: A possible model of archaic introgression based on the latest analysis using second-generation sequencing.
Figure 2: Alternative human origin models that fit existing fossil evidence on the basis of either phylogenetic or pedigree-based mutation rates.
Figure 3: Second-generation sequencing in ancient Europeans.

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Acknowledgements

The authors thank J. Watkins, F. Mendez, A. Woerner, J. Burger and D. Caramelli for their comments on the manuscript and L. Johnstone for her help in figure 3. Support for this work was provided by the US National Institutes of Health to M.F.H. (R01_HG005226).

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Correspondence to Michael F. Hammer.

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Supplementary information

Supplementary information S1 (box)

Inferring changes in effective population size (Ne). (PDF 221 kb)

Supplementary information S2 (box)

Construction of the PCA plot of aDNA samples (Figure 3B). (PDF 186 kb)

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Glossary

Mitochondrial DNA

(mtDNA). A circular piece of non-recombining DNA of ~16,000 bp that is found in the mitochondrion and that is inherited exclusively from the maternal parent.

Non-recombining portion of the Y chromosome

(NRY). The middle ~95% of the Y chromosome that is passed from father to son and that does not undergo recombination during meiosis, thereby allowing inheritance of genetic ancestry to be traced exclusively down the paternal line.

Uniparentally inherited systems

Genetic material in organisms with distinct sexes that is passed on to offspring through inheritance only from one sex; that is, mitochondrial DNA and the non-recombining portion of the Y chromosome.

Short tandem repeat

(STR). A DNA sequence that contains a variable number (typically ≤50) of tandem repeated short sequence motifs of 2–6 bp, such as (GATA)n.

Population structure

The distribution of individuals into partially isolated local subpopulations or demes that are interconnected by migration.

Phylogeographical approaches

Methods that use the geographical distribution of genetic lineages, which are deduced from phylogenetic methods, to infer the demographic history of a set of individuals or populations.

Model-based inference methods

Analyses that specify demographic models, investigate the model that best fits the genetic data and infer parameters of interest (such as population size changes, divergence times and migration events) for the best-fitting model.

Anatomically modern humans

(AMHs). Individuals that are classified as Homo sapiens on the basis of the set of morphological characteristics that distinguish them from other, now extinct, members of the genus Homo (that is, archaic humans). According to the fossil record, AMHs emerged ~ 200,000–150,000 years ago.

Reciprocal monophyly

The phenomenon whereby all lineages within a species are genealogically closer to each other (in this context, on the basis of the sharing of common genetic variants) than they are to any lineages in other species that are considered in a phylogeny.

Clades

Groups of entities (such as genes or organisms) in a phylogenetic tree that have all arisen from a common ancestor.

Introgression

Gene flow between populations or species whose individuals hybridize.

Range expansions

Increases in the geographical distribution of a population through time from some region of origin.

Linkage disequilibrium

(LD). The nonrandom association of alleles that are carried at different loci. LD can arise for various reasons (such as novel mutations, genetic drift, natural selection and admixture), but recombination is the main process that removes it.

Founder events

Scenarios in which a new population is founded by a small number of incoming individuals. Similarly to a bottleneck, the founder effect severely reduces genetic diversity and increases the effect of random drift.

Admixture

Gene flow between two or more groups that have been separated for a long enough period of time to be genetically distinct.

Coalescence

A process that describes the genealogy of chromosomes or genes under a particular demographic model. The genealogy is constructed backwards in time and starts with the present-day sample. Lineages coalesce until the most recent common ancestor of the sample is reached.

Melanesians

The putative indigenous inhabitants of the islands of Melanesia in the Pacific, which is a subregion of Oceania that includes the modern-day countries Papua New Guinea, Solomon Islands, Vanuatu and Fiji.

D statistic

A statistic that detects admixture by examining patterns of allele sharing between single genomes of two sister populations and a more diverged third population that has putatively experienced gene flow to a greater degree with one of these two sister populations since they diverged; an outgroup is also used to determine the ancestral state of alleles.

Derived alleles

Alleles that arise in a population following the mutation of an ancestral allele. Ancestral alleles can be distinguished from derived alleles, as the ancestral allele will typically be present in an outgroup species (for example, the chimpanzee sequence when examining variants in humans).

Allele frequency spectrum

(AFS). A distribution of the counts of single-nucleotide polymorphisms with a given frequency in a single population or in multiple populations.

'Ghost' archaic hominin

Archaic hominin species for which there is no current available genetic sequence data, although there may be fossil evidence. Such species may improve the current fit, or at least provide an equally good fit, when considering demographic models that examine anatomically modern humans and archaic species for which there are sequence data.

Effective population size

(Ne). Formulated by Wright in 1931, Ne reflects the size of an idealized population that would experience genetic drift in the same way as an actual population under study. Ne can be lower (and occasionally higher) than census population size owing to various factors, including variance in reproductive success, a history of population bottlenecks and reduced recombination.

Haplogroups

Specific lineages of either mitochondrial DNA or non-recombining portion of the Y chromosome that are defined by a genealogically concordant combination of alleles (that is, haplotypes) at slowly evolving binary markers.

Levantine corridor

A narrow land route that lies between the coast of the Mediterranean Sea to the west and Arabian deserts to the east, which connects Africa to Europe and Asia. It is seen as a common prehistorical bidirectional route of movement for both flora and fauna (including the genus Homo).

D4P statistic

A statistic that is similar to the D statistic in that it examines patterns of allele sharing as it relates to deviations of congruence between gene trees and population trees. However, D4P does not rely on an outgroup, such as chimpanzees, to infer ancestral and derived states and uses variants that are found in at least two of four test genomes, each from a different population. It is thus, among other things, more robust to sequencing errors.

Identity by state

Alleles that are the same. These alleles may or may not be identical by descent owing to the possibility of multiple mutation events.

Pairwise sequentially Markovian coalescent model

A specialization of the sequentially Markovian coalescent model that considers only two chromosomes.

Cline

In the context of genetic data, the exhibition of regular and directional variation in genotype or allele frequencies across a geographical region.

Demic diffusion model

A migration model in which populations diffuse into new geographical areas and displace or interbreed with indigenous populations.

Isolation-by-distance model

A model in which the amount of gene flow between two locations decreases as a function of distance. At equilibrium, this model predicts that genetic differentiation increases as a function of geographical distance.

Identity by descent

The phenomenon whereby two alleles are a copy of the same allele that was carried in an ancestral individual.

Principal component analysis

(PCA). A statistical method that is used to simplify a complex data set by transforming a series of correlated variables into a smaller number of uncorrelated variables known as principal components.

Singleton

A genetic variant that is present in only a single chromosome from the sample analysed.

Sequentially Markovian coalescent model

A simplification of the standard model of coalescence with recombination, such that the addition of crossover events while moving along the genome has a Markovian structure; that is, the addition of recombination at a given position along the genome depends only on the previous genealogy in which recombination was considered, rather than on the whole ancestral recombination graph from the beginning of the chromosome.

Haplotype-phased

Pertaining to DNA sequence or genotyping data in an individual for which the combination of alleles contributed by each parental chromosome is resolved.

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Veeramah, K., Hammer, M. The impact of whole-genome sequencing on the reconstruction of human population history. Nat Rev Genet 15, 149–162 (2014). https://doi.org/10.1038/nrg3625

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