Research

Research Overview

Archaic Introgression and Human Population History

Inferring the very ancient admixture events between Archaic hominins and us

Complex Traits Genetics in Recently Admixed Populations

Modeling changes in the genetic underpinnings of complex traits as a result of recent admixture

Dynamic Admixed Genomes in Non-human Study Systems

Studying the ongoing dynamics of admixture through the lens of fast evolving non-human species

Methods Development in Population Genetics

Machine Learning and statistical methods development for inferring genomic parameters and signals

Studying admixture is fundamental to understanding the diversity in modern humans today. At the Zhang Lab, we integrate evolutionary, genomic, and computational tools to solve outstanding questions pertaining to human evolution and health. We currently have four parallel lines of research that study admixture and natural selection from complementary perspectives:

Archaic introgression and its influence on modern human population history

The discovery of Denisovans is one of the most exciting findings in human evolution in the past decade. However, as of today, more questions have been asked than the ones being answered regarding this mysterious archaic hominin. The striking similarity between sequences of the EPAS1 gene in Denisovans and modern Tibetans suggested adaptive introgression that facilitated high altitude adaptation, while the time and geographic ranges where the contact between species was made remain unknown.

In a recent work, we leveraged information of the EPAS1 gene in modern Tibetans, and determined the history of interactions between Denisovans and the ancestors of our species, via extensive applications of statistical methods and simulations. We show that among the multiple pulses of Denisovan introgression in East Asia, the beneficial EPAS1 haplotype was introduced by a group highly alike the Denisovan individual from the Altai mountains, while the positive selection on this gene did not start until after a long period being a neutral variant.

Our ongoing work on the adaptive introgression focuses on the Americas. Previous studies including a work from our group identified a number of candidate adaptive introgression genes in Central and South American populations, which is highly exciting because there is no evidence of archaic hominins in the New world. Therefore, the only sources where the American populations received archaic ancestry are through the ancestral Asian populations via the peopling of the Americas, or through post-colonial admixture with modern Europeans and other non-African populations. This provides a unique opportunity to study the co-shaping process of genetic diversity in the Americas by archaic introgression and recent population history. We are currently applying ARG methods to infer the adaptive introgression history on the candidate genes, which will reveal details on the population history, the existence of a pre-colonization bottleneck, and post-colonization admixtures.

Reference:
1. Zhang et al., The history and evolution of the Denisovan-EPAS1 haplotype in Tibetans. Proceedings of the National Academy of Sciences Jun 2021, 118 (22) e2020803118; DOI: 10.1073/pnas.2020803118
2. Zhang*, Zhang* et al., Denisovans and Homo sapiens on the Tibetan Plateau: dispersals and adaptations. Trends in Ecology and Evolution, Jan 2022. https://doi.org/10.1016/j.tree.2021.11.004 *These authors contributed equally
3. Findley A, Zhang X, Boye C, Lin Y, Kalita C, Barreiro L, Lohmueller K, Pique-Regi R, Luca F. A signature of Neanderthal introgression on molecular mechanisms of environmental responses. PLOS Genetics 17(9): e1009493. https://doi.org/10.1371/journal.pgen.1009493

Complex traits genetics in recently admixed human populations

In recent years, studies have made significant progress in understanding the polygenic basis and local adaptations of a wide range of complex traits and common genetic diseases. In one of my side projects during PhD, I applied the polygenic score and the Qst/Fst method to worldwide modern and ancient human populations for detecting selection signals on a number of anthropometric traits, as an attempt to extend our understanding on the polygenic adaptation on human height in modern Europeans. However, the reliability of the clear signal of positive selection on height, as well as the interpretation of GWAS-based analyses in general, were vehemently challenged by the failure of replicating the signals in newly released UK biobank data. It was revealed that the previous evidences were strongly confounded by population stratification. Furthermore, multiple studies also suggested poor transferability of polygenic scores across populations, especially in diverse, admixed populations.

We are currently using a mixed approach to study how recent admixture in human population influenced the genetics of complex traits. We leverage simulation methods and empirical biobank data to systematically understand mechanisms that change GWAS performance and the genetic architecture of complex traits in admixed populations. We are also developing a machine learning method that infers the genomic distribution of dominance effects, which will help us develop non-additive models to improve polygenic risk predictions with a special focus on underrepresented diverse human populations that experienced recent admixtures.

Reference:
1. Berg, Zhang, Coop. Polygenic Adaptation has Impacted the Evolution of Multiple Anthropometric Traits. biorXiv, 2018
2. Berg, Harpak, ... Zhang, ... Pritchard, Coop. Reduced Signal for Polygenic Adaptation of Height in UK Biobank. eLife, 2019.

The dynamic process of admixture revealed by rapidly evolving non-human organisms

During the first two decades of the 21st century, two malaria parasites had been confirmed to be naturally transmissible between humans and macaques in Southeast Asia, in contrast to the previous belief that Plasmodium parasites are highly host-specific. It was suspected that the occurrence of zoonotic malaria was due to close proximity between humans and wild animals, however the exact prevalence of zoonotic parasites in macaque populations was unclear.

In my PhD research, I led a pioneering project to characterize the epidemiology of zoonotic malaria in their natural hosts long-tailed macaques (Macaca fascicularis) in Southeast Asia. I reported infections in their Laotian population for the first time, which enabled public health organizations in related area to target prevention acts in human population under threat of infection. I further investigated the demographic histories of the long-tailed macaque populations, and showed strikingly distinct malaria susceptibilities among individuals driven by previously unknown admixture with rhesus macaques (Macaca mulatta). Revealing the association between susceptibility and admixture had effectively prevented misuse of research animals with unclear ancestry in critical anti-malaria medical research. This project also had shed light on future identification of vital genes under selection in human and non-human primates, which may reveal candidate regions for precision medicine and personalized treatment.

My lab is currently developing a novel approach to study the real-time dynamics of admixture using organisms with short generation gaps. Due to the long generation time in humans, traditional studies of human admixture primarily focused on present-day populations. My lab aims to bypass this limitation and study the longitudinal process of admixture using model organisms including Drosophila species that enables an experimental evolution framework, and admixed nonhuman primate populations that allow us to study the change in fitness and complex traits.

Reference:
1. Zhang et al., Distribution and prevalence of malaria parasites among long-tailed macaques (Macaca fascicularis) in regional populations across Southeast Asia. Malaria Journal, 2016
2. Zhang et al., Ancestry, Plasmodium cynomolgi prevalence and rhesus macaque admixture in cynomolgus macaques (Macaca fascicularis) bred for export in Chinese breeding farms. Journal of Medical Primatology, 2017
3. Zhang et al., Genetic Characterization of a Captive Colony of Pigtailed Macaques (Macaca nemestrina). Journal of American Association for Laboratory Animal Science, 2017

Methods development in Population Genetics

Developing novel statistical methods is of critical value in the application of population genetics in anthropological research, as the quality and quantity of available data are rapidly changing. Many studies since the 2010s have revealed candidate genes in worldwide populations being adaptively introgressed from archaic hominins, while recently studies also have suggested that recessive deleterious variants private to donor populations can create heterosis upon admixture. Without a beneficial mutation, this process can lead to signatures similar to adaptive introgression, and it was not clear whether heterosis can change the detection of current statistical methods for adaptive introgression.

In one of our recent articles, we find that signals of adaptive introgression remain robust in most but two genes, HLA and HYAL2. And it turns out their susceptibility to high false positive rates are predominantly contributed by two factors: high exon density and low recombination rate, simultaneously. Overall, recessive deleterious variants affect the power of statistical methods detecting adaptive introgression and should be included in the null models, which is especially important for studying organisms with compact genomic structures.

Recently, we developed a novel machine learning method called MaLAdapt to detect genome-wide adaptive introgression. Leveraging information from a large number of population genetic summary statistics, this method is especially powerful at detecting adaptive introgression with mild beneficial effects, including selection on standing archaic variation, and is robust to confounding mechanisms such as non-introgressed selection sweeps, heterosis, and demographic mis-specifications. MaLAdapt revealed novel adaptive introgression candidate regions in all non-African populations that were previously undetected.

We are now working with developing several new methods in population genetics that address a variety of questions focusing on the inference of ghost introgression, adaptive introgression in nonhuman organisms, and accurate prediction of complex trait phenotypes in admixed populations.

Reference:
1. Zhang et al., The impact of recessive deleterious variants on signals of adaptive introgression in human populations, GENETICS 2020 vol. 215 no. 3 799-812
2. Zhang et al.. MaLAdapt reveals novel targets of adaptive introgression from Neanderthals and Denisovans in worldwide human populations. Molecular Biology and Evolution, Volume 40, Issue 1, Jan 2023