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The MHC Express : = Evolution of an Immune-Related Gene Family Across the Primates.

Record Type:	Language materials, manuscript : Monograph/item
Title/Author:	The MHC Express :/
Reminder of title:	Evolution of an Immune-Related Gene Family Across the Primates.
Author:	Fortier, Alyssa Lyn.
Description:	1 online resource (354 pages)
Notes:	Source: Dissertations Abstracts International, Volume: 85-06, Section: B.
Contained By:	Dissertations Abstracts International85-06B.
Subject:	T cell receptors. -
Online resource:	click for full text (PQDT)
ISBN:	9798381028362

The MHC Express : = Evolution of an Immune-Related Gene Family Across the Primates.
Fortier, Alyssa Lyn.

The MHC Express :Evolution of an Immune-Related Gene Family Across the Primates. - 1 online resource (354 pages)

Source: Dissertations Abstracts International, Volume: 85-06, Section: B.

Thesis (Ph.D.)--Stanford University, 2023.

Includes bibliographical references

The adaptive immune system is highly specific to particular pathogens and "remembers" all past pathogen encounters, allowing an organism to fight those pathogens faster in the future . Central to this system is the Major Histocompatibility Complex (MHC), a large genomic locus whose "classical" gene products help T-cells distinguish which cells are normal and which are infected. With this key role in self-versus-non-self recognition, it is no surprise that the MHC is repeatedly identified in genome-wide-association studies and is critical to matching donors for organ transplantation.The MHC (and adaptive immunity) originated in the ancestor of the jawed vertebrates, and is so critical to pathogen defense that it has been subject to intense selective pressure . In the past few hundred million years, the MHC has evolved numerous genes involved in diverse functions- from presenting antigens to T-cells, to mediating maternal-fetal immunotolerance, to helping other molecules with peptide loading, to serving as general indicators of cellular distress. Many of these genes undergo rapid birth-and-death evolution and are highly plastic, even turning over multiple times in the 60-million-year history of the primates. On the other hand, some genes have clear orthology within and beyond the primates . To make matters even more complex, the "classical" genes are ridiculously polymorphic, and some of these alleles are so extraordinarily long-lived that they even predate speciation events (known as trans-species polymorphism). These observations point to a mix of both directional and balancing selection shaping the MHC region, giving the gene family a rich and complex evolutionary history.This history, along with the clinical relevance of the MHC, has sparked over 40 years of research into the evolution of the region. However, the large number of genes with unclear orthology, extreme polymorphism within genes, and long-range linkage disequilibrium makes the MHC challenging to study. Small pieces of the MHC-evolution puzzle are scattered across hundreds of papers, and it is dicult to get the full picture when the data and methods in these papers vary so widely. Thus, I aimed to revisit MHC evolution systematically with more data and modern methods, with the hopes of unifying and expanding upon the large existing body of work.Through Bayesian phylogenetic analysis of the entire MHC gene family using sequences from more than 100 species (focusing on primates), I present a comprehensive view of MHC evolution both between and within genes, addressing both rapid evolution and long-term balancing selection.First, I determine the evolutionary relationships between members of the family broadly, resolving unknowns about the origins of various genes. Additionally, I discover many instances of interand intra-locus gene conversion, especially within exons that encode the molecules' peptide-binding region. I then focus on individual clades within the gene family, exploring the relationships between paralogous genes and alleles within genes. I identify widespread trans-species polymorphism within the classical genes, with alleles in the genes MHC-DQA1, MHC-DQB1, and MHC-DRB1 being maintained for over 30 million years! Additionally, I discover that rapidly-evolving sites are primarily located in the peptide-binding regions of classical genes but are distributed throughout the entire gene in non-classical genes. Together, this work provides a comprehensive picture of the evolution of the MHC in primates, which will serve as a reference for future MHC researchers and inform the evolution of our species more broadly.

Electronic reproduction.
Ann Arbor, Mich. :
ProQuest,
2024

Mode of access: World Wide Web

ISBN: 9798381028362Subjects--Topical Terms:

1475730
T cell receptors.
Index Terms--Genre/Form:

554714
Electronic books.

The MHC Express : = Evolution of an Immune-Related Gene Family Across the Primates.
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520 $a The adaptive immune system is highly specific to particular pathogens and "remembers" all past pathogen encounters, allowing an organism to fight those pathogens faster in the future . Central to this system is the Major Histocompatibility Complex (MHC), a large genomic locus whose "classical" gene products help T-cells distinguish which cells are normal and which are infected. With this key role in self-versus-non-self recognition, it is no surprise that the MHC is repeatedly identified in genome-wide-association studies and is critical to matching donors for organ transplantation.The MHC (and adaptive immunity) originated in the ancestor of the jawed vertebrates, and is so critical to pathogen defense that it has been subject to intense selective pressure . In the past few hundred million years, the MHC has evolved numerous genes involved in diverse functions- from presenting antigens to T-cells, to mediating maternal-fetal immunotolerance, to helping other molecules with peptide loading, to serving as general indicators of cellular distress. Many of these genes undergo rapid birth-and-death evolution and are highly plastic, even turning over multiple times in the 60-million-year history of the primates. On the other hand, some genes have clear orthology within and beyond the primates . To make matters even more complex, the "classical" genes are ridiculously polymorphic, and some of these alleles are so extraordinarily long-lived that they even predate speciation events (known as trans-species polymorphism). These observations point to a mix of both directional and balancing selection shaping the MHC region, giving the gene family a rich and complex evolutionary history.This history, along with the clinical relevance of the MHC, has sparked over 40 years of research into the evolution of the region. However, the large number of genes with unclear orthology, extreme polymorphism within genes, and long-range linkage disequilibrium makes the MHC challenging to study. Small pieces of the MHC-evolution puzzle are scattered across hundreds of papers, and it is dicult to get the full picture when the data and methods in these papers vary so widely. Thus, I aimed to revisit MHC evolution systematically with more data and modern methods, with the hopes of unifying and expanding upon the large existing body of work.Through Bayesian phylogenetic analysis of the entire MHC gene family using sequences from more than 100 species (focusing on primates), I present a comprehensive view of MHC evolution both between and within genes, addressing both rapid evolution and long-term balancing selection.First, I determine the evolutionary relationships between members of the family broadly, resolving unknowns about the origins of various genes. Additionally, I discover many instances of interand intra-locus gene conversion, especially within exons that encode the molecules' peptide-binding region. I then focus on individual clades within the gene family, exploring the relationships between paralogous genes and alleles within genes. I identify widespread trans-species polymorphism within the classical genes, with alleles in the genes MHC-DQA1, MHC-DQB1, and MHC-DRB1 being maintained for over 30 million years! Additionally, I discover that rapidly-evolving sites are primarily located in the peptide-binding regions of classical genes but are distributed throughout the entire gene in non-classical genes. Together, this work provides a comprehensive picture of the evolution of the MHC in primates, which will serve as a reference for future MHC researchers and inform the evolution of our species more broadly.
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