Tuesday, November 8, 2016

New haplotype representations in the LRC_KIR region on chromosome 19q13.4

The KIR (Killer cell immunoglobulin-like receptor) gene cluster is a region of approximately 150 kb within the Leukocyte Receptor Complex (LRC) on human chromosome 19q13.4 (CM000681.2: 50900001-58617616). The KIR family is highly divergent, with multiple haplotypes differing in gene content, and with individual genes exhibiting allelic variation. Only a few KIR genes are conserved between humans and chimpanzees, the closest living relatives to humans. The GRCh38 assembly includes 35 representations for the LRC-KIR region as alternate loci scaffolds in addition to the chromosomal sequence (ALT_REF_LOCI in LRC-KIR region). David Roe and colleagues (personal communication) recently sequenced a diverse panel of KIR haplotypes with the goal to report novel structures and to demonstrate the ability to fully characterize KIR haplotypes, even across long repetitive sequences in diploid individuals.The sequences for these 15 haplotypes are derived from 8 individuals (one is homozygous for the haplotype). While all 15 haplotypes represent new allelic variations, 6 of the 15 haplotype structures exhibit novel numbers and types of KIR genes (rows highlighted black in Table 1).

cA01-tA01 KV575246.1 NW_016107300.1
cA01-tA01 KV575247.1 NW_016107301.1
cA01-tA01 KV575248.1 NW_016107302.1
cA01-tB04 KV575249.1 NW_016107303.1
cA01-tB01 KV575250.1 NW_016107304.1
cA01-tA01 KV575251.1 NW_016107305.1
cB05-tA01 KV575252.1 NW_016107306.1
cA01-tA01 KV575253.1 NW_016107307.1
cA03-tB02 KV575254.1 NW_016107308.1
cA01-tA01 KV575255.1 NW_016107309.1
cB01-tB01 KV575256.1 NW_016107310.1
cA04 KV575257.1 NW_016107311.1
cB04-tB03 KV575258.1 NW_016107312.1
cA01-tA01 KV575259.1 NW_016107313.1
cB02-tA01 KV575260.1 NW_016107314.1
Table 1: Haplotype identifier, GenBank and RefSeq accession numbers for the 15 new KIR haplotypes reported in GRCh38.p8; rows highlighted in black indicate new haplotype structures. The haplotype name shown in Table 1 is reported in the Comment section in both GenBank and RefSeq records.

All 15 new haplotypes have been added to the reference assembly in GRCh38 patch release 8 (GRCh38.p8) as novel patches. Figure 1 provides a comparison of the KIR gene content of reference chr. 19 and the novel patch haplotype "cA04". The novel patch NW_016107311.1 represents a new KIR haplotype which contains only 4 KIR genes as compared to 9 KIR genes in the reference chr. 19.

Figure 1: LRC_KIR region on chromosome 19q13.4.  Top: KIR region on reference chromosome 19, the 4 genes in common between the reference chromosome and the novel patch labeled in red and the 5 genes missing in haplotype "cA04" boxed in blue. Bottom: KIR gene represntation in haplotype "cA04" (KU645198.1). This haplotype has only 4 KIR gene (labeled in red) as compared to the reference chr. 19. The blue bars represent the tiling path of chr. 19 (NC_000019.10) and the gray bar represents novel sequences. In the gray track representing alignment of KIR haplotype to chr. 19, the solid horizontal red line indicates the region of KIR haplotype "cA04" that has no alignments to reference chromosome, the small vertical red bars indicate mismatches, and site of missing sequence in “cA04” is highlighted as deletion. 

The Roe group assisted the GRC with the alignments of the patch scaffolds to the reference chromosome to ensure gene relationships were properly represented. The KIR region is one of the most variable regions of the human genome. Donor selection based on KIR genotyping of multiple best matched HLA has improved transplantation outcome, and certain combinations of KIR-HLA genotypes have been reported in association with autoimmune diseases and malignancies. The newly represented KIR haplotypes provide additional resources for haplotype analysis of KIR genes.