Reflections on Ancestral Haplotypes: Medical Genomics, Evolution, and Human Individuality

Abstract

The major histocompatibility complex (MHC), once labelled the "sphinx of immunology" by Jan Klein, provides powerful challenges to evolutionary thinking. This essay highlights the main discoveries that established the block ancestral haplotype structure of the MHC and the wider genome, focusing on the work by the Perth (Australia) group, led by Roger Dawkins, and the Boston group, led by Chester Alper and Edmond Yunis. Their achievements have been overlooked in the rush to sequence the first and subsequent drafts of the human genome. In Caucasoids, where most of the detailed work has been done, about 70% of all known allelic MHC diversity can be accounted for by 30 or so ancestral haplotypes (AHs), or conserved sequences of many mega-bases, and their recombinants. The block haplotype structure of the genome, as shown for the MHC (and other genetic regions), is a story that needs to be understood in its own right, particularly given the promotion of the "HapMap" project and single nucleotide polymorphism (SNP) linkage disequilibrium (LD) analysis, which has been wrongly touted as the only way to pinpoint those genes that are important in genetic disorders or other desired (qualitative) characteristics.

Soma‐to‐germline feedback is implied by the extreme polymorphism at IGHV relative to MHC

“…These data have presented clinical immunologists and molecular geneticists with profound enigmas concerning linkage disequilibrium phenomena that contradict much conventional genetic thinking. These issues, in their historical perspective, have been critically evaluated and reviewed at great length in a recent book . Particularly confounding is the existence in unrelated individuals of high frequency (≥1%) MHC ancestral haplotypes (≥4 Mb) inherited en bloc from remote ancestors over thousands of generations .…”

“…Schematic outline of the genetic map defining the major histocompatibility complex on human chromosome 6p21.3. Adapted from Steele , Parham and Ohta , and Trowsdale and Knight . The tables show the numbers of distinct HLA alleles recently accepted by the IMGT database ( www.imgt.org release .15.0 17 Jan 2014 ).…”

“…Alper and colleagues show that SNP‐LD analyses fail to detect any of the well established disease‐associated MHC conserved extended (ancestral) haplotypes . This failure may reflect an incorrect genomic model ; realistic models may need to be factored into GWAS analysis.…”

Dangers of Adhering to an Obsolete Paradigm: Could Zika Virus Lead to a Reversal of Human Evolution?

“…For a more accurate description of metazoan evolution we now need to turn briefly to another important development in evolutionary genomics over the past 35 years -the discovery of ancestral haplotypes (AH) [13,[29][30][31][32]. One of us (EJS) has recently reviewed the scientific history of these discoveries [33,34].…”

HLA-A*29:01-B*07:05-C*15:29*DRB1*10:01-DQB1*05:01, a deduced probable human leukocyte antigen haplotype in association with a human leukocyte antigen-C low-incidence allele C*15:29 in Taiwanese individuals

“…The major histocompatibility complex (MHC), including human leukocyte antigen (HLA) genes, is located in chromosome 6p21. It contains crucial genes for crucial immune responses and other genes with nonimmunological roles [1]. The HLA genetic system, located in the MHC Class I and Class II regions, displays the highest degree of polymorphism of any functional genetic complex with medical impact representing a landmark for the development of preventive and predictive medicine.…”