Genomic evolution and polymorphism: Segmental duplications and haplotypes at 108 regions on 21 chromosomes

Abstract

We describe here extensive, previously unknown, genomic polymorphism in 120 regions, covering 19 autosomes and both sex chromosomes. Each contains duplication within multigene clusters. Of these, 108 are extremely polymorphic with multiple haplotypes. We used the genomic matching technique (GMT), previously used to characterise the major histocompatibility complex (MHC) and regulators of complement activation (RCA). This genome-wide extension of this technique enables the examination of many underlying cis, trans and epistatic interactions responsible for phenotypic differences especially in relation to individuality, evolution and disease susceptibility. The extent of the diversity could not have been predicted and suggests a new model of primate evolution based on conservation of polymorphism rather than de novo mutation.

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

“…Their most striking and controversial property is that each AH is highly conserved , devoid of both spontaneous mutation and recombination events, and retroviral infections are strongly implicated as a major driver in their genesis [13,34,35]. Such PFB are evident in other mammalian species [36] and have been detected at some 108 locations across the human genome [37]. On the latter they are often found in highly duplicated regions encompassing many genes and are peppered with retro-elements and other likely regulatory DNA sequences viz.…”

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

“…The alpha and beta blocks cover the telomeric HLA-A and HLA-B Class I regions of antigen presentation molecules (HLA-A, -C, -B; cytotoxic T cell activation), the gamma block covers the central region encoding some of the complement proteins amongst other non-HLA gene families (C2, Bf [CFB], C4A, C4B), and the centromeric delta block covers the D region encoding HLA Class II antigen presentation molecules (DR, DQ; helper and regulator T cell activation). Recombination and assortment, when it occurs at meiosis, takes place at a higher frequency between these blocks, such that MHC diversity is maintained in the human population by the shuffling of existing PFBs or pretested polymorphism (Dawkins et al 1999(Dawkins et al , 2013McLure et al 2013). Perhaps greater than 70% of all Caucasoid MHC diversity can be accounted for by about 22 common AHs and their recombinant blocks , although estimates by others put this number as low as 30% (Degli-Esposti et al 1992;Yunis et al 2003).…”

“…However, the full elucidation of the haplotype concept was left to the Perth group, led by Roger Dawkins, and the Boston group of Chester Alper and Edmond Yunis, who separately and together from the late 1970s published the extensive serologic, genetic, and molecular data underpinning the idea. The Perth group developed, then established, the ancestral haplotype (AH) concept as an accurate description of the polymorphic block haplotype structure of the mammalian genome (Dawkins et al 1982(Dawkins et al , 1983(Dawkins et al , 1999(Dawkins et al , 2013Degli-Esposti et al 1992;Kelly et al 1985;McLure et al 2005aMcLure et al , 2005bMcLure et al , 2013Tokunaga et al 1988;Williamson et al 2011). The Boston group described the same genomic regions associated with complex diseases within the major histocompatibility complex (MHC), and in 1983 named them "conserved extended haplotypes" (CEHs; Alper et al 1982Alper et al , 1986Awdeh et al 1983Awdeh et al , 1985Raum et al 1976Raum et al , 1979Raum et al , 1984Yunis et al 2003;Alper et al 2006).…”

“…Thus, apart from the misappropriation issue, the other take-home message of this essay is the misguided way clinical and population scientists have gone about looking for such genetic markers using genome-wide association studies. The simple "genes as beads on a string" model of traditional population genetics-developed in fruit flies, earth worms, and simple fungi-is no longer applicable to the wider human and mammalian genome, which has evolved a very different "quantal" structure (Longman-Jacobsen et al 2003;McLure et al 2013). Here genes occur in conserved clusters in extensively duplicated polymorphic regions (Dawkins et al 1999;McLure et al 2013).…”

“…The simple "genes as beads on a string" model of traditional population genetics-developed in fruit flies, earth worms, and simple fungi-is no longer applicable to the wider human and mammalian genome, which has evolved a very different "quantal" structure (Longman-Jacobsen et al 2003;McLure et al 2013). Here genes occur in conserved clusters in extensively duplicated polymorphic regions (Dawkins et al 1999;McLure et al 2013). Given the importance of AHs/CEHs to human health, this essay also raises the question of why the simple demonstration of the polymerase chain reaction-based genomic matching technique (GMT) has not been embraced as a cheap, reliable, and life-saving medical diagnostic procedure, particularly in bone marrow transplantation (Gaudieri et al 2001;Kitcharoen et al 2006;Tay et al 1995aTay et al , 1995bWitt et al 2000).…”