Mark Stoneking

Genetic history of an archaic hominin group from Denisova Cave in Siberia

Using DNA extracted from a finger bone found in Denisova Cave in southern Siberia, we have sequenced the genome of an archaic hominin to about 1.9-fold coverage. This individual is from a group that shares a common origin with Neanderthals. This population was not involved in the putative gene flow from Neanderthals into Eurasians; however, the data suggest that it contributed 4–6% of its genetic material to the genomes of present-day Melanesians. We designate this hominin population ‘Denisovans’ and suggest that it may have been widespread in Asia during the Late Pleistocene epoch. A tooth found in Denisova Cave carries a mitochondrial genome highly similar to that of the finger bone. This tooth shares no derived morphological features with Neanderthals or modern humans, further indicating that Denisovans have an evolutionary history distinct from Neanderthals and modern humans.

Neandertal DNA sequences and the origin of modern humans

DNA was extracted from the Neandertal-type specimen found in 1856 in western Germany. By sequencing clones from short overlapping PCR products, a hitherto unknown mitochondrial (mt) DNA sequence was determined. Multiple controls indicate that this sequence is endogenous to the fossil. Sequence comparisons with human mtDNA sequences, as well as phylogenetic analyses, show that the Neandertal sequence falls outside the variation of modern humans. Furthermore, the age of the common ancestor of the Neandertal and modern human mtDNAs is estimated to be four times greater than that of the common ancestor of human mtDNAs. This suggests that Neandertals went extinct without contributing mtDNA to modern humans.

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.

Whole-genome sequence variation, population structure and demographic history of the Dutch population

Whole-genome sequencing enables complete characterization of genetic variation, but geographic clustering of rare alleles demands many diverse populations be studied. Here we describe the Genome of the Netherlands (GoNL) Project, in which we sequenced the whole genomes of 250 Dutch parent-offspring families and constructed a haplotype map of 20.4 million single-nucleotide variants and 1.2 million insertions and deletions. The intermediate coverage (∼13×) and trio design enabled extensive characterization of structural variation, including midsize events (30–500 bp) previously poorly catalogued and de novo mutations. We demonstrate that the quality of the haplotypes boosts imputation accuracy in independent samples, especially for lower frequency alleles. Population genetic analyses demonstrate fine-scale structure across the country and support multiple ancient migrations, consistent with historical changes in sea level and flooding. The GoNL Project illustrates how single-population whole-genome sequencing can provide detailed characterization of genetic variation and may guide the design of future population studies.

A New Approach for Using Genome Scans to Detect Recent Positive Selection in the Human Genome

Genome-wide scanning for signals of recent positive selection is essential for a comprehensive and systematic understanding of human adaptation. Here, we present a genomic survey of recent local selective sweeps, especially aimed at those nearly or recently completed. A novel approach was developed for such signals, based on contrasting the extended haplotype homozygosity (EHH) profiles between populations. We applied this method to the genome single nucleotide polymorphism (SNP) data of both the International HapMap Project and Perlegen Sciences, and detected widespread signals of recent local selection across the genome, consisting of both complete and partial sweeps. A challenging problem of genomic scans of recent positive selection is to clearly distinguish selection from neutral effects, given the high sensitivity of the test statistics to departures from neutral demographic assumptions and the lack of a single, accurate neutral model of human history. We therefore developed a new procedure that is robust across a wide range of demographic and ascertainment models, one that indicates that certain portions of the genome clearly depart from neutrality. Simulations of positive selection showed that our tests have high power towards strong selection sweeps that have undergone fixation. Gene ontology analysis of the candidate regions revealed several new functional groups that might help explain some important interpopulation differences in phenotypic traits.

Global diversity in the human salivary microbiome

The human salivary microbiome may play a role in diseases of the oral cavity and interact with microbiomes from other parts of the human body (in particular, the intestinal tract), but little is known about normal variation in the salivary microbiome. We analyzed 14,115 partial ( approximately 500 bp) 16S ribosomal RNA (rRNA) sequences from saliva samples from 120 healthy individuals (10 individuals from each of 12 worldwide locations). These sequences could be assigned to 101 known bacterial genera, of which 39 were not previously reported from the human oral cavity; phylogenetic analysis suggests that an additional 64 unknown genera are present. There is high diversity in the salivary microbiome within and between individuals, but little geographic structure. Overall, approximately 13.5% of the total variance in the composition of genera is due to differences among individuals, which is remarkably similar to the fraction of the total variance in neutral genetic markers that can be attributed to differences among human populations. Investigation of some environmental variables revealed a significant association between the genetic distances among locations and the distance of each location from the equator. Further characterization of the enormous diversity revealed here in the human salivary microbiome will aid in elucidating the role it plays in human health and disease, and in the identification of potentially informative species for studies of human population history.

Human mtDNA and Y-chromosome variation is correlated with matrilocal versus patrilocal residence

Genetic differences among human populations are usually larger for the Y chromosome than for mtDNA. One possible explanation is the higher rate of female versus male migration due to the widespread phenomenon of patrilocality, in which the woman moves to her mates residence after marriage. To test this hypothesis, we compare mtDNA and Y-chromosome variation in three matrilocal (in which the man moves to his mates residence after marriage) and three patrilocal groups among the hill tribes of northern Thailand. Genetic diversity in these groups shows a striking correlation with residence pattern, supporting the role of sex-specific migration in influencing human genetic variation.

A melanocortin 1 receptor allele suggests varying pigmentation among Neanderthals

The melanocortin 1 receptor (MC1R) regulates pigmentation in humans and other vertebrates. Variants of MC1R with reduced function are associated with pale skin color and red hair in humans of primarily European origin. We amplified and sequenced a fragment of the MC1R gene (mc1r) from two Neanderthal remains. Both specimens have a mutation that was not found in ∼3700 modern humans analyzed. Functional analyses show that this variant reduces MC1R activity to a level that alters hair and/or skin pigmentation in humans. The impaired activity of this variant suggests that Neanderthals varied in pigmentation levels, potentially on the scale observed in modern humans. Our data suggest that inactive MC1R variants evolved independently in both modern humans and Neanderthals.

Dual origins of the Japanese: common ground for hunter-gatherer and farmer Y chromosomes

AbstractHistoric Japanese culture evolved from at least two distinct migrations that originated on the Asian continent. Hunter-gatherers arrived before land bridges were submerged after the last glacial maximum (>12,000 years ago) and gave rise to the Jomon culture, and the Yayoi migration brought wet rice agriculture from Korea beginning ∼2,300 years ago. A set of 81 Y chromosome single nucleotide polymorphisms (SNPs) was used to trace the origins of Paleolithic and Neolithic components of the Japanese paternal gene pool, and to determine the relative contribution of Jomon and Yayoi Y chromosome lineages to modern Japanese. Our global sample consisted of >2,500 males from 39 Asian populations, including six populations sampled from across the Japanese archipelago. Japanese populations were characterized by the presence of two major (D and O) and two minor (C and N) clades of Y chromosomes, each with several sub-lineages. Haplogroup D chromosomes were present at 34.7% and were distributed in a U-shaped pattern with the highest frequency in the northern Ainu and southern Ryukyuans. In contrast, haplogroup O lineages (51.8%) were distributed in an inverted U-shaped pattern with a maximum frequency on Kyushu. Coalescent analyses of Y chromosome short tandem repeat diversity indicated that haplogroups D and C began their expansions in Japan ∼20,000 and ∼12,000 years ago, respectively, while haplogroup O-47z began its expansion only ∼4,000 years ago. We infer that these patterns result from separate and distinct genetic contributions from both the Jomon and the Yayoi cultures to modern Japanese, with varying levels of admixture between these two populations across the archipelago. The results also support the hypothesis of a Central Asian origin of Jomonese ancestors, and a Southeast Asian origin of the ancestors of the Yayoi, contra previous models based on morphological and genetic evidence.

Genetic variation of recent Alu insertions in human populations

The Alu family of intersperesed repeats is comprised of ovr 500,000 members which may be divided into discrete subfamilies based upon mutations held in common between members. Distinct subfamilies of Alu sequences have amplified within the human genome in recent evolutionary history. Several individual Alu family members have amplified so recently in human evolution that they are variable as to presence and absence at specific loci within different human populations. Here, we report on the distribution of six polymorphic Alu insetions in a survey of 563 individuals from 14 human population groups across several continents. Our results indicate that these polymorphic Alu insertions probably have an African origin and that there is a much smaller amount of genetic variation between European populations than that found between other populations groups.