Biomedical subjects

Daniel Garrigan

Publications and source records attributed to Daniel Garrigan.

7 recordsLinked to original sources

PubMed2006

Reconstructing human origins in the genomic era.

Analyses of recently acquired genomic sequence data are leading to important insights into the early evolution of anatomically modern humans, as well as into the more recent demographic processes that accompanied the global radiation of Homo sapiens. Some of the new results contradict early, but still influential, conclusions that were based on analyses of gene trees from mitochondrial DNA and Y-chromosome sequences. In this review, we discuss the different genetic and statistical methods that are available for studying human population history, and identify the most plausible models of human evolution that can accommodate the contrasting patterns observed at different loci throughout the genome.

Africa↗

PubMed2005

Deep haplotype divergence and long-range linkage disequilibrium at xp21.1 provide evidence that humans descend from a structured ancestral population.

Fossil evidence links human ancestry with populations that evolved from modern gracile morphology in Africa 130,000-160,000 years ago. Yet fossils alone do not provide clear answers to the question of whether the ancestors of all modern Homo sapiens comprised a single African population or an amalgamation of distinct archaic populations. DNA sequence data have consistently supported a single-origin model in which anatomically modern Africans expanded and completely replaced all other archaic hominin populations. Aided by a novel experimental design, we present the first genetic evidence that statistically rejects the null hypothesis that our species descends from a single, historically panmictic population. In a global sample of 42 X chromosomes, two African individuals carry a lineage of noncoding 17.5-kb sequence that has survived for >1 million years without any clear traces of ongoing recombination with other lineages at this locus. These patterns of deep haplotype divergence and long-range linkage disequilibrium are best explained by a prolonged period of ancestral population subdivision followed by relatively recent interbreeding. This inference supports human evolution models that incorporate admixture between divergent African branches of the genus Homo.

Biological Evolution↗

PubMed2004

Evidence for archaic Asian ancestry on the human X chromosome.

The human RRM2P4 pseudogene has a pattern of nucleotide polymorphism that is unlike any locus published to date. A gene tree constructed from a 2.4-kb fragment of the RRM2P4 locus sequenced in a sample of 41 worldwide humans clearly roots in East Asia and has a most-recent common ancestor approximately 2 Myr before present. The presence of this basal lineage exclusively in Asia results in higher nucleotide diversity among non-Africans than among Africans. A global survey of a single-nucleotide polymorphism that is diagnostic for the basal, Asian lineage in 570 individuals shows that it occurs at frequencies up to 53% in south China, whereas only one of 177 surveyed Africans carries this archaic lineage. We suggest that this ancient lineage is a remnant of introgressive hybridization between expanding anatomically modern humans emerging from Africa and archaic populations in Eurasia.

Africa↗

PubMed2004

Contrasting patterns of Y chromosome variation in Ashkenazi Jewish and host non-Jewish European populations.

The molecular basis of more than 25 genetic diseases has been described in Ashkenazi Jewish populations. Most of these diseases are characterized by one or two major founder mutations that are present in the Ashkenazi population at elevated frequencies. One explanation for this preponderance of recessive diseases is accentuated genetic drift resulting from a series of dispersals to and within Europe, endogamy, and/or recent rapid population growth. However, a clear picture of the manner in which neutral genetic variation has been affected by such a demographic history has not yet emerged. We have examined a set of 32 binary markers (single nucleotide polymorphisms; SNPs) and 10 microsatellites on the non-recombining portion of the Y chromosome (NRY) to investigate the ways in which patterns of variation differ between Ashkenazi Jewish and their non-Jewish host populations in Europe. This set of SNPs defines a total of 20 NRY haplogroups in these populations, at least four of which are likely to have been part of the ancestral Ashkenazi gene pool in the Near East, and at least three of which may have introgressed to some degree into Ashkenazi populations after their dispersal to Europe. It is striking that whereas Ashkenazi populations are genetically more diverse at both the SNP and STR level compared with their European non-Jewish counterparts, they have greatly reduced within-haplogroup STR variability, especially in those founder haplogroups that migrated from the Near East. This contrasting pattern of diversity in Ashkenazi populations is evidence for a reduction in male effective population size, possibly resulting from a series of founder events and high rates of endogamy within Europe. This reduced effective population size may explain the high incidence of founder disease mutations despite overall high levels of NRY diversity.

Chromosomes, Human, Y↗

PubMed2004

MtDNA evidence for a genetic bottleneck in the early history of the Ashkenazi Jewish population.

The relative roles of natural selection and accentuated genetic drift as explanations for the high frequency of more than 20 Ashkenazi Jewish disease alleles remain controversial. To test for the effects of a maternal bottleneck on the Ashkenazi Jewish population, we performed an extensive analysis of mitochondrial DNA (mtDNA) hypervariable segment 1 (HVS-1) sequence and restriction site polymorphisms in 565 Ashkenazi Jews from different parts of Europe. These patterns of variation were compared with those of five Near Eastern (n=327) and 10 host European (n=849) non-Jewish populations. Only four mtDNA haplogroups (Hgs) (defined on the basis of diagnostic coding region RFLPs and HVS-1 sequence variants) account for approximately 70% of Ashkenazi mtDNA variation. While several Ashkenazi Jewish mtDNA Hgs appear to derive from the Near East, there is also evidence for a low level of introgression from host European non-Jewish populations. HVS-1 sequence analysis revealed increased frequencies of Ashkenazi Jewish haplotypes that are rare or absent in other populations, and a reduced number of singletons in the Ashkenazi Jewish sample. These diversity patterns provide evidence for a prolonged period of low effective size in the history of the Ashkenazi population. The data best fit a model of an early bottleneck (approximately 100 generations ago), perhaps corresponding to initial migrations of ancestral Ashkenazim in the Near East or to Europe. A genetic bottleneck followed by the recent phenomenon of rapid population growth are likely to have produced the conditions that led to the high frequency of many genetic disease alleles in the Ashkenazi population.

DNA Mutational Analysis↗

PubMed2004

Heterogeneous patterns of variation among multiple human x-linked Loci: the possible role of diversity-reducing selection in non-africans.

Studies of human DNA sequence polymorphism reveal a range of diversity patterns throughout the genome. This variation among loci may be due to natural selection, demographic influences, and/or different sampling strategies. Here we build on a continuing study of noncoding regions on the X chromosome in a panel of 41 globally sampled humans representing African and non-African populations by examining patterns of DNA sequence variation at four loci (APXL, AMELX, TNFSF5, and RRM2P4) and comparing these patterns with those previously reported at six loci in the same panel of 41 individuals. We also include comparisons with patterns of noncoding variation seen at five additional X-linked loci that were sequenced in similar global panels. We find that, while almost all loci show a reduction in non-African diversity, the magnitude of the reduction varies substantially across loci. The large observed variance in non-African levels of diversity results in the rejection of a neutral model of molecular evolution with a multi-locus HKA test under both a constant size and a bottleneck model. In non-Africans, some loci harbor an excess of rare mutations over neutral equilibrium predictions, while other loci show no such deviation in the distribution of mutation frequencies. We also observe a positive relationship between recombination rate and frequency spectra in our non-African, but not in our African, sample. These results indicate that a simple out-of-Africa bottleneck model is not sufficient to explain the observed patterns of sequence variation and that diversity-reducing selection acting at a subset of loci and/or a more complex neutral model must be invoked.

Black or African American↗

PubMed2003

Perspective: detecting adaptive molecular polymorphism: lessons from the MHC.

In the 1960s, when population geneticists first began to collect data on the amount of genetic variation in natural populations, balancing selection was invoked as a possible explanation for how such high levels of molecular variation are maintained. However, the predictions of the neutral theory of molecular evolution have since become the standard by which cases of balancing selection may be inferred. Here we review the evidence for balancing selection acting on the major histocompatibility complex (MHC) of vertebrates, a genetic system that defies many of the predictions of neutrality. We apply many widely used tests of neutrality to MHC data as a benchmark for assessing the power of these tests. These tests can be categorized as detecting selection in the current generation, over the history of populations, or over the histories of species. We find that selection is not detectable in MHC datasets in every generation, population, or every evolutionary lineage. This suggests either that selection on the MHC is heterogeneous or that many of the current neutrality tests lack sufficient power to detect the selection consistently. Additionally, we identify a potential inference problem associated with several tests of neutrality. We demonstrate that the signals of selection may be generated in a relatively short period of microevolutionary time, yet these signals may take exceptionally long periods of time to be erased in the absence of selection. This is especially true for the neutrality test based on the ratio of nonsynonymous to synonymous substitutions. Inference of the nature of the selection events that create such signals should be approached with caution. However, a combination of tests on different time scales may overcome such problems.

Adaptation, Biological↗