Archaic introgression and variation in pharmacogenes and implications for local adaptation

Modern humans carry Neanderthal and Denisovan (archaic) genome elements which may have been a result of environmental adaptation. These effects may be particularly evident in pharmacogenes - genes responsible for the processing of exogenous substances such as food, pollutants, and medications. However, the health implications and contribution of archaic ancestry in pharmacogenes of modern humans remains understudied. We characterize eleven key cytochrome P450 (CYP450) genes involved in drug metabolizing reactions in three Neanderthal and one Denisovan individuals and examine archaic introgression in modern human populations. We infer the metabolizing efficiency of these eleven genes in archaic individuals and show important genetic differences relative to modern human variants. We identify archaic-specific SNVs in each CYP450 gene, including some that are potentially damaging, which may result in altered metabolism in modern human people carrying these variants. We highlight four genes which display interesting patterns of archaic variation: CYP2B6 - we find a large number of unique variants in the Vindija Neanderthal, some of which are shared with a small subset of African modern humans; CYP2C9 - containing multiple variants that are shared between Europeans and Neanderthals; CYP2A6*12 - a variant defined by a hybridization event that was found in humans and Neanderthals, suggesting the recombination event predates both species; and CYP2J2 - in which we hypothesize a Neanderthal variant was re-introduced in non-African populations by archaic admixture. The genetic variation identified in archaic individuals imply environmental pressures that may have driven CYP450 gene evolution.

Refining models of archaic admixture in Eurasia with ArchaicSeeker 2.0

We developed a method, ArchaicSeeker 2.0, to identify introgressed hominin sequences and model multiple-wave admixture. The new method enabled us to discern two waves of introgression from both Denisovan-like and Neanderthal-like hominins in present-day Eurasian populations and an ancient Siberian individual. We estimated that an early Denisovan-like introgression occurred in Eurasia around 118.8–94.0 thousand years ago (kya). In contrast, we detected only one single episode of Denisovan-like admixture in indigenous peoples eastern to the Wallace-Line. Modeling ancient admixtures suggested an early dispersal of modern humans throughout Asia before the Toba volcanic super-eruption 74 kya, predating the initial peopling of Asia as proposed by the traditional Out-of-Africa model. Survived archaic sequences are involved in various phenotypes including immune and body mass (e.g., ZNF169), cardiovascular and lung function (e.g., HHAT), UV response and carbohydrate metabolism (e.g., HYAL1/HYAL2/HYAL3), while “archaic deserts” are enriched with genes associated with skin development and keratinization.

On the Apportionment of Archaic Human Diversity

The apportionment of human genetic diversity within and between populations has been measured to understand human relatedness and demographic history. Likewise, the distribution of archaic ancestry in modern populations can be leveraged to better understand the interaction between our species and its archaic relatives, and the impact of natural selection on archaic segments of the human genome. Resolving these interactions can be difficult, as archaic variants in modern populations have also been shaped by genetic drift, bottlenecks, and gene flow. Here, we investigate the apportionment of archaic variation in Eurasian populations. We find that archaic genome coverage at the individual- and population-level present unique patterns in modern human population: South Asians have an elevated count of population-unique archaic SNPs, and Europeans and East Asians have a higher degree of archaic SNP sharing, indicating that population demography and archaic admixture events had distinct effects in these populations. We confirm previous observations that East Asians have more Neanderthal ancestry than Europeans at an individual level, but surprisingly Europeans have more Neandertal ancestry at a population level. In comparing these results to our simulated models, we conclude that these patterns likely reflect a complex series of interactions between modern humans and archaic populations.

Introgression, hominin dispersal and megafaunal survival in Late Pleistocene Island Southeast Asia

The hominin fossil record of Island Southeast Asia (ISEA) indicates that at least two endemic ‘super-archaic’ species – Homo luzonensis and H. floresiensis – were present around the time anatomically modern humans (AMH) arrived in the region >50,000 years ago. Contemporary human populations carry signals consistent with interbreeding events with Denisovans in ISEA – a species that is thought to be more closely related to AMH than the super-archaic endemic ISEA hominins. To query this disparity between fossil and genetic evidence, we performed a comprehensive search for super-archaic introgression in >400 modern human genomes. Our results corroborate widespread Denisovan ancestry in ISEA populations but fail to detect any super-archaic admixture signals. By highlighting local megafaunal survival east of the Wallace Line as a potential signature of deep, pre-H. sapiens hominin-faunal interaction, we propose that this understudied region may hold the key to unlocking significant chapters in Denisovan prehistory.

Denisovan introgression has shaped the immune system of present-day Papuans

Modern humans have substantially admixed with multiple archaic hominins. New Guineans, in particular, owe up to 5% of their genome to Denisovans, a sister group to Neanderthals, whose remains have only been identified in Siberia and Tibet. Unfortunately, the biological and evolutionary significance of these events remain poorly understood. Here we investigate the function of archaic alleles of both Denisovan and Neanderthal ancestry characterised within a previously published set of 72 genomes from individuals of Papuan genetic ancestry living in the island of New Guinea. By comparing the distribution of archaic and modern human variants, we are able to assess the consequences of archaic admixture across a multitude of different cell types and functional elements. We find that archaic alleles are often located within cis-regulatory elements and transcribed regions of the genome, suggesting that they are actively involved in a wide range of cellular regulatory processes. We identify 39,269 high-confidence Denisovan variants that fall within annotated cis-regulatory elements and have the potential to alter the affinity of multiple transcription factors to their cognate DNA motifs, highlighting a likely mechanism by which introgressed DNA can impact phenotypes in present-day humans. Additionally, we detect a consistent signal across Denisovan variants of strong involvement in immune-related processes. Lastly, we show how such regulatory effects might underlie some of the observed gene expression differences between multiple Indonesian populations carrying varying amount of Denisovan DNA. Together, these data provide support for the hypothesis that, despite their broadly deleterious nature, archaic alleles actively contribute to modern human phenotypic diversity and might have facilitated early adaptation to non-African environments.

Legofit: Estimating Population History from Genetic Data

BackgroundOur current understanding of archaic admixture in humans relies on statistical methods with large biases, whose magnitudes depend on the sizes and separation times of ancestral populations. To avoid these biases, it is necessary to estimate these parameters simultaneously with those describing admixture. Genetic estimates of population histories also confront problems of statistical identifiability: different models or different combinations of parameter values may fit the data equally well. To deal with this problem, we need methods of model selection and model averaging, which are lacking from most existing software.ResultsThe Legofit software package allows simultaneous estimation of parameters describing admixture and other aspects of population history. It includes facilities for data manipulation, estimation, model selection, and model averaging. It outperforms several statistical methods that have been widely used to study archaic admixture in humans.

Impact and evolutionary determinants of Neanderthal introgression on transcriptional and post-transcriptional regulation

Archaic admixture is increasingly recognized as an important source of diversity in modern humans, with Neanderthal haplotypes covering 1-3% of the genome of present-day Eurasians. Recent work has shown that archaic introgression has contributed to human phenotypic diversity, mostly through the regulation of gene expression. Yet, the mechanisms through which archaic variants alter gene expression, and the forces driving the introgression landscape at regulatory regions remain elusive. Here, we explored the impact of archaic introgression on transcriptional and post-transcriptional regulation, focusing on promoters and enhancers across 127 different tissues as well as microRNA-mediated regulation. Although miRNAs themselves harbor few archaic variants, we found that some of these variants may have a strong impact on miRNA-mediated gene regulation. Enhancers were by far the regulatory elements most affected by archaic introgression, with one third of the tissues tested presenting significant enrichments. Specifically, we found strong enrichments of archaic variants in adipose-related tissues and primary T cells, even after accounting for various genomic and evolutionary confounders such as recombination rate and background selection. Interestingly, we identified signatures of adaptive introgression at enhancers of some key regulators of adipogenesis, raising the interesting hypothesis of a possible adaptation of early Eurasians to colder climates. Collectively, this study sheds new light onto the mechanisms through which archaic admixture have impacted gene regulation in Eurasians and, more generally, increases our understanding of the contribution of Neanderthals to the regulation of acquired immunity and adipose homeostasis in modern humans.