Population Genomic Architecture: Conserved Polymorphic Sequences (CPSs), Not Linkage Disequilibrium

Editorial

26 January 2023

Editorial: Population genomic architecture: Conserved polymorphic sequences (CPSs), not linkage disequilibrium

Chester A. Alper

Roger L. Dawkins

Jerzy K. Kulski

Charles E. Larsen

and

Sally S. Lloyd

1,640 views

1 citations

Editors

Chester A. Alper

Boston Children's Hospital, Harvard Medical School

Jerzy K. Kulski

University of Western Australia

Charles E. Larsen

Boston Children's Hospital, Harvard Medical School

Sally S. Lloyd

C Y O’Connor ERADE Village Foundation

Roger L. Dawkins

C Y O’Connor ERADE Village Foundation

Impact

Review

28 February 2022

Speciation of Genes and Genomes: Conservation of DNA Polymorphism by Barriers to Recombination Raised by Mismatch Repair System

Miroslav Radman

A drawing of the mechanistic principle for the editing of homologous recombination by mismatch repair proteins: Reversal of an attempt to initiate homologous recombination between non-identical (homeologous) sequences. MMR+ stands for mismatch recognition and repair proteins; REC+ for recombination proteins at the DNA strand invasion step; MM are mismatched or unmatched bases; MEPS is “minimal efficient processing segment”, i.e., minimal sufficient block of strict sequence identity required to initiate strand exchange (ref 13). RecBCD nuclease is known to degrade the free-ended (red) DNA that did not succeed in recombination (Štambuk and Radman, 1998) precluding repeated recombination attempts at the already edited site. See text and refs. (Shen and Huang, 1986; Radman, 1989; Kowalczykowski et al., 1994; Worth et al., 1994; Štambuk and Radman, 1998; Wiktor et al., 2021).

Some basic aspects of human and animal biology and evolution involve the establishment of biological uniqueness of species and individuals within their huge variety. The discrimination among closely related species occurs in their offspring at the level of chromosomal DNA sequence homology, which is required for fertility as the hallmark of species. Biological identification of individuals, i.e., of their biological “self”, occurs at the level of protein sequences presented by the MHC/HLA complex as part of the immune system that discriminates non-self from self. Here, a mechanistic molecular model is presented that can explain how DNA sequence divergence and the activity of key mismatch repair proteins, MutS and MutL, lead to 1) genetic separation of closely related species (sympatric speciation) (Fitch and Ayala, Proceedings of the National Academy of Sciences, 1994, 91, 6717–6720), 2) the stability of genomes riddled by diverged repeated sequences, and 3) conservation of highly polymorphic DNA sequence blocks that constitute the immunological self. All three phenomena involve suppression of recombination between diverged homologies, resulting in prevention of gene sharing between closely related genomes (evolution of new species) as well as sequence sharing between closely related genes within a genome (e.g., evolution of immunoglobulin, MHC, and other gene families bearing conserved polymorphisms).

3,971 views

5 citations

CPSs are inherited unchanged from distant ancestors. Blocks are conserved because sequence differences prevent recombination. Some reshuffling is possible when a homozygous block is present. An example is highlighted in yellow where the 123 haplotype has recombined with the 222 haplotype because it is homozygous at the second block thereby creating a 223 haplotype.

General Commentary

11 November 2022

Commentary: Conserved polymorphic sequences protect themselves for future challenges

Roger L. Dawkins

and

Sally S. Lloyd

1,207 views

1 citations

Original Research

07 July 2021

Haplotypic Associations and Differentiation of MHC Class II Polymorphic Alu Insertions at Five Loci With HLA-DRB1 Alleles in 12 Minority Ethnic Populations in China

Yina Cun

, 7 more and

Yufeng Yao

The analysis of polymorphic variations in the human major histocompatibility complex (MHC) class II genomic region on the short-arm of chromosome 6 is a scientific enquiry to better understand the diversity in population structure and the effects of evolutionary processes such as recombination, mutation, genetic drift, demographic history, and natural selection. In order to investigate associations between the polymorphisms of HLA-DRB1 gene and recent Alu insertions (POALINs) in the HLA class II region, we genotyped HLA-DRB1 and five Alu loci (AluDPB2, AluDQA2, AluDQA1, AluDRB1, AluORF10), and determined their allele frequencies and haplotypic associations in 12 minority ethnic populations in China. There were 42 different HLA-DRB1 alleles for ethnic Chinese ranging from 12 alleles in the Jinuo to 28 in the Yugur with only DRB1^∗08:03, DRB1^∗09:01, DRB1^∗12:02, DRB1^∗14:01, DRB1^∗15:01, and DRB1^∗15:02 present in all ethnic groups. The POALINs varied in frequency between 0.279 and 0.514 for AluDPB2, 0 and 0.127 for AluDQA2, 0.777 and 0.995 for AluDQA1, 0.1 and 0.455 for AluDRB1 and 0.084 and 0.368 for AluORF10. By comparing the data of the five-loci POALIN in 13 Chinese ethnic populations (including Han-Yunnan published data) against Japanese and Caucasian published data, marked differences were observed between the populations at the allelic or haplotypic levels. Five POALIN loci were in significant linkage disequilibrium with HLA-DRB1 in different populations and AluDQA1 had the highest percentage association with most of the HLA-DRB1 alleles, whereas the nearby AluDRB1 indel was strongly haplotypic for only DRB1^∗01, DRB1^∗10, DRB1^∗15 and DRB1^∗16. There were 30 five-locus POALIN haplotypes inferred in all populations with H5 (no Alu insertions except for AluDQA1) and H21 (only AluDPB2 and AluDQA1 insertions) as the two predominant haplotypes. Neighbor joining trees and principal component analyses of the Alu and HLA-DRB1 polymorphisms showed that genetic diversity of these genomic markers is associated strongly with the population characteristics of language family, migration and sociality. This comparative study of HLA-DRB1 alleles and multilocus, lineage POALIN frequencies of Chinese ethnic populations confirmed that POALINs whether investigated alone or together with the HLA class II alleles are informative genetic and evolutionary markers for the identification of allele and haplotype lineages and genetic variations within the same and/or different populations.

2,838 views

8 citations

Mini Review

06 August 2021

The Path to Conserved Extended Haplotypes: Megabase-Length Haplotypes at High Population Frequency

Chester A. Alper

3,118 views

5 citations

Single-nucleotide polymorphism (SNP) density plots of six pairs of MHC class II haplotypes from HLA-DRB1 to COL11A2. The genomic region and distances for the haplotype sequences are indicated at the top of the Figure with a gene map and an abbreviated TE map highlighting U1 and a few LTR, MER and HERV elements. The six SNP plots are comparisons between (A) 1_ DRB1∗01:01/DQA1∗01:01/DQB1∗05:01:01/MTCO3P1∗09 versus 48_ DRB1∗04:06/DPA1∗02:02/MTCO3P1∗08; and then 51_DRB1∗15:01:01:01/DQA1∗01:02/DQB1∗06:02/MTCO3P1∗02 versus (B) 90_ DRB1∗15:01/DQA1∗01:02/DQB1∗06:02/MTCO3P1∗02, (C) 41_ DRB1∗04:01/DQA1∗03:01/DQB1∗03:02/MTCO3P1∗08, (D) 62_ DRB1∗15:02/DQA1∗01:03/DQB1∗06:01/MTCO3P1∗04, (E) 68_ DRB1∗11:03/DPA1∗01:03/DPB1∗04:02/MTCO3P1∗03, and (F) 84_ DRB1∗15:01:01/DQA1∗01:02:01/DQB1∗06:02/MTCO3P1∗02. The Y-axis presents the number of SNPs per 500 nucleotides (window size). The X-axis shows the SNP positions (SNPs/500 nucleotides) in a block of 632829 nucleotides from HLA-DRB1 to COL11A2 (A–F). The letter ‘A’ along the X-axis marks regions of sequence gaps, poor assembly, inversions or long runs of unspecified nucleotides. ‘A1’ is the position of a MER11/LTR5 indel (TE ID #37 and #38) between 76999 and 79305; ‘A2’ is the position of a 4562-bp LTR5/L1PA10 indel (TE ID #41); and A3 is the position of a 9324-bp indel at 77368-86691 that includes the presence or absence of MER4 and L1PA10 together with the THE1A-AluY-THE1A and LTR5 (see TE IDs #12, #40 and #41 in Table 3 and Supplementary Table 3). The dashed vertical lines mark the SNP-density crossover (XO) points between haplotype pairs. The boxed number is the XO sequence position for sequence ID_51.

Original Research

28 May 2021

Haplotype Shuffling and Dimorphic Transposable Elements in the Human Extended Major Histocompatibility Complex Class II Region

Jerzy K. Kulski

, 1 more and

Takashi Shiina

The major histocompatibility complex (MHC) on chromosome 6p21 is one of the most single-nucleotide polymorphism (SNP)-dense regions of the human genome and a prime model for the study and understanding of conserved sequence polymorphisms and structural diversity of ancestral haplotypes/conserved extended haplotypes. This study aimed to follow up on a previous analysis of the MHC class I region by using the same set of 95 MHC haplotype sequences downloaded from a publicly available BioProject database at the National Center for Biotechnology Information to identify and characterize the polymorphic human leukocyte antigen (HLA)-class II genes, the MTCO3P1 pseudogene alleles, the indels of transposable elements as haplotypic lineage markers, and SNP-density crossover (XO) loci at haplotype junctions in DNA sequence alignments of different haplotypes across the extended class II region (∼1 Mb) from the telomeric PRRT1 gene in class III to the COL11A2 gene at the centromeric end of class II. We identified 42 haplotypic indels (20 Alu, 7 SVA, 13 LTR or MERs, and 2 indels composed of a mosaic of different transposable elements) linked to particular HLA-class II alleles. Comparative sequence analyses of 136 haplotype pairs revealed 98 unique XO sites between SNP-poor and SNP-rich genomic segments with considerable haplotype shuffling located in the proximity of putative recombination hotspots. The majority of XO sites occurred across various regions including in the vicinity of MTCO3P1 between HLA-DQB1 and HLA-DQB3, between HLA-DQB2 and HLA-DOB, between DOB and TAP2, and between HLA-DOA and HLA-DPA1, where most XOs were within a HERVK22 sequence. We also determined the genomic positions of the PRDM9-recombination suppression sequence motif ATCCATG/CATGGAT and the PRDM9 recombination activation partial binding motif CCTCCCCT/AGGGGAG in the class II region of the human reference genome (NC_ 000006) relative to published meiotic recombination positions. Both the recombination and anti-recombination PRDM9 binding motifs were widely distributed throughout the class II genomic regions with 50% or more found within repeat elements; the anti-recombination motifs were found mostly in L1 fragmented repeats. This study shows substantial haplotype shuffling between different polymorphic blocks and confirms the presence of numerous putative ancestral recombination sites across the class II region between various HLA class II genes.

4,263 views

15 citations

Segregation analysis of the 5 families with one T1D subject showing the MHC long-range haplotypes. In dotted lines are offsprings diagnosed with T1D. (A) Family 2 haplotypes, II.iii is diagnosed with T1D. (B) Family 22 haplotypes, II.iii is diagnosed with T1D. (C) Family 23 haplotypes, II.iii is diagnosed with T1D.

Original Research

30 June 2021

Segregation Analysis of Genotyped and Family-Phased, Long Range MHC Classical Class I and Class II Haplotypes in 5 Families With Type 1 Diabetes Proband in the United Arab Emirates

Guan K. Tay

, 5 more and

Habiba Alsafar

3,767 views

6 citations

Original Research

18 January 2021

SNP-Density Crossover Maps of Polymorphic Transposable Elements and HLA Genes Within MHC Class I Haplotype Blocks and Junction

Jerzy K. Kulski

, 1 more and

Takashi Shiina

The genomic region (~4 Mb) of the human major histocompatibility complex (MHC) on chromosome 6p21 is a prime model for the study and understanding of conserved polymorphic sequences (CPSs) and structural diversity of ancestral haplotypes (AHs)/conserved extended haplotypes (CEHs). The aim of this study was to use a set of 95 MHC genomic sequences downloaded from a publicly available BioProject database at NCBI to identify and characterise polymorphic human leukocyte antigen (HLA) class I genes and pseudogenes, MICA and MICB, and retroelement indels as haplotypic lineage markers, and single-nucleotide polymorphism (SNP) crossover loci in DNA sequence alignments of different haplotypes across the Olfactory Receptor (OR) gene region (~1.2 Mb) and the MHC class I region (~1.8 Mb) from the GPX5 to the MICB gene. Our comparative sequence analyses confirmed the identity of 12 haplotypic retroelement markers and revealed that they partitioned the HLA-A/B/C haplotypes into distinct evolutionary lineages. Crossovers between SNP-poor and SNP-rich regions defined the sequence range of haplotype blocks, and many of these crossover junctions occurred within particular transposable elements, lncRNA, OR12D2, MUC21, MUC22, PSORS1A3, HLA-C, HLA-B, and MICA. In a comparison of more than 250 paired sequence alignments, at least 38 SNP-density crossover sites were mapped across various regions from GPX5 to MICB. In a homology comparison of 16 different haplotypes, seven CEH/AH (7.1, 8.1, 18.2, 51.x, 57.1, 62.x, and 62.1) had no detectable SNP-density crossover junctions and were SNP poor across the entire ~2.8 Mb of sequence alignments. Of the analyses between different recombinant haplotypes, more than half of them had SNP crossovers within 10 kb of LTR16B/ERV3-16A3_I, MLT1, Charlie, and/or THE1 sequences and were in close vicinity to structurally polymorphic Alu and SVA insertion sites. These studies demonstrate that (1) SNP-density crossovers are associated with putative ancestral recombination sites that are widely spread across the MHC class I genomic region from at least the telomeric OR12D2 gene to the centromeric MICB gene and (2) the genomic sequences of MHC homozygous cell lines are useful for analysing haplotype blocks, ancestral haplotypic landscapes and markers, CPSs, and SNP-density crossover junctions.

6,179 views

15 citations

Original Research

15 July 2020

Identification of Novel Alleles and Structural Haplotypes of Major Histocompatibility Complex Class I and DRB Genes in Domestic Cat (Felis catus) by a Newly Developed NGS-Based Genotyping Method

Masaharu Okano

, 6 more and

Takashi Shiina

The major histocompatibility complex (MHC) is a highly polymorphic and duplicated genomic region that encodes transplantation and immune regulatory molecules. Although it is well-known that particular MHC allelic polymorphisms and haplotypes are genetically relate to immune-mediated diseases detailed information of the cat MHC (Feline Leukocyte Antigen; FLA) genetic and haplotypic structure and diversity is limited in comparison to humans and many other species. In this study, to better understand the degree and types of allele and allelic haplotype diversity of FLA-class I (FLA-I) and FLA-DRB loci in domestic cats, we identified six expressible FLA-I loci in peripheral white blood cells by in silico estimation of the coding exons and NGS-based amplicon sequencing using five unrelated cats. We then used a newly developed NGS-based genotyping method to genotype and annotate 32 FLA-I and 16 FLA-DRB sequences in two families of 20 domestic cats. A total of 14 FLA-I and seven FLA-DRB were identified as novel polymorphic sequences. Phylogenetic analyses grouped the sequences into six FLA-I (FLA-E/H/K, FLA-A, FLA-J, FLA-L, FLA-O and a tentatively named FLA-E/H/K_Rec) and four FLA-DRB (FLA-DRB1, FLA-DRB3, FLA-DRB4, and FLA-DRB5) lineages. Pedigree analysis of two cat families revealed eight distinct FLA structural haplotypes (Class I – DRB) with five to eight FLA-I and two to three FLA-DRB transcribed loci per haplotype. It is evident that the eight FLA haplotypes were generated by gene duplications and deletions, and rearrangements by genetic recombination with the accumulation and/or inheritance of novel polymorphisms. These findings are useful for further genetic diversity analysis and disease association studies among cat breeds and in veterinary medicine.

4,319 views

11 citations

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