Biology subjects

Fortier, A. L.

Publications and source records attributed to Fortier, A. L..

4 recordsLinked to original sources

bioRxiv2024

The Primate Major Histocompatibility Complex: An Illustrative Example of Gene Family Evolution

Gene families are groups of evolutionarily-related genes. One large gene family that has experienced rapid evolution lies within the Major Histocompatibility Complex (MHC), whose proteins serve critical roles in innate and adaptive immunity. Across the [~]60 million year history of the primates, some MHC genes have turned over completely, some have changed function, some have converged in function, and others have remained essentially unchanged. Past work has typically focused on identifying MHC alleles within particular species or comparing gene content, but more work is needed to understand the overall evolution of the gene family across species. Thus, despite the immunologic importance of the MHC and its peculiar evolutionary history, we lack a complete picture of MHC evolution in the primates. We readdress this question using sequences from dozens of MHC genes and pseudogenes spanning the entire primate order, building a comprehensive set of gene and allele trees with modern methods. Overall, we find that the Class I gene subfamily is evolving much more quickly than the Class II gene subfamily, with the exception of the Class II MHC-DRB genes. We also pay special attention to the often-ignored pseudogenes, which we use to reconstruct different events in the evolution of the Class I region. We find that despite the shared function of the MHC across species, different species employ different genes, haplotypes, and patterns of variation to achieve a successful immune response. Our trees and extensive literature review represent the most comprehensive look into primate MHC evolution to date.

evolutionary biology↗

bioRxiv2022

Ancient Trans-Species Polymorphism at the Major Histocompatibility Complex in Primates

Classical genes within the Major Histocompatibility Complex (MHC) are responsible for peptide presentation to T cells, thus playing a central role in immune defense against pathogens. These genes are subject to strong selective pressures including both balancing and directional selection, resulting in exceptional genetic diversity--thousands of alleles per gene in humans. Moreover, some allelic lineages appear to be shared between primate species, a phenomenon known as trans-species polymorphism (TSP) or incomplete lineage sorting, which is rare in the genome overall. However, despite the clinical and evolutionary importance of MHC diversity, we currently lack a full picture of primate MHC evolution. In particular, we do not know to what extent genes and allelic lineages are retained across speciation events. To start addressing this gap, we explore variation across genes and species in our companion paper (Fortier and Pritchard, 2025) and here we explore variation within individual genes. We used Bayesian phylogenetic methods to determine the extent of TSP at 17 MHC genes, including classical and non-classical Class I and Class II genes. We find strong support for ancient TSP in 7 of 10 classical genes, including--remarkably--between humans and old-world monkeys in MHC-DQB1. In addition to the long-term persistence of ancient lineages, we additionally observe rapid evolution at nucleotides encoding the proteins peptide-binding domains. The most rapidly-evolving amino acid positions are extremely enriched for autoimmune and infectious disease associations. Together, these results suggest complex selective forces--arising from differential peptide binding--that drive short-term allelic turnover within lineages while also maintaining deeply divergent lineages for at least 31 million years in some cases.

evolutionary biology↗

bioRxiv2020

Human-Genetic Ancestry Inference and False Positives in Forensic Familial Searching

In forensic familial search methods, a query DNA profile is tested against a database to determine if the query profile represents a close relative of a database entrant. One challenge for familial search is that the calculations may require specification of allele frequencies for the unknown population from which the query profile has originated. Allele-frequency misspecification can substantially inflate false-positive rates compared to use of allele frequencies drawn from the same population as the query profile. Here, we use ancestry inference on the query profile to circumvent the high false-positive rates that result from highly misspecified allele frequencies. In particular, we perform ancestry inference on the query profile and make use of allele frequencies based on its inferred genetic ancestry. In a test for sibling matches on profiles that represent unrelated individuals, we demonstrate that false-positive rates for familial search with use of ancestry inference to specify the allele frequencies are similar to those seen when allele frequencies align with the population of origin of a profile. Because ancestry inference is possible to perform on query profiles, the extreme allele-frequency misspecifications that produce the highest false-positive rates can be avoided. We discuss the implications of the results in the context of concerns about the forensic use of familial searching.

genetics↗

bioRxiv2019

DFEnitely different: Genome-wide characterization of differences in mutation fitness effects between populations

The effect of a mutation on fitness may differ between populations depending on environmental and genetic context, but little is known about the factors that underlie such differences. To quantify genome-wide correlations in mutation fitness effects, we developed a novel concept called a joint distribution of fitness effects (DFE) between populations. We then proposed a new statistic w to measure the DFE correlation between populations. Using simulation, we showed that inferring the DFE correlation from the joint allele frequency spectrum is statistically precise and robust. Using population genomic data, we inferred DFE correlations of populations in humans, Drosophila melanogaster, and wild tomatoes. In these specices, we found that the overall correlation of the joint DFE was inversely related to genetic differentiation. In humans and D. melanogaster, deleterious mutations had a lower DFE correlation than tolerated mutations, indicating a complex joint DFE. Altogether, the DFE correlation can be reliably inferred, and it offers extensive insight into the genetics of population divergence.

evolutionary biology↗