Haplosaurus computes protein haplotypes for use in precision drug design

Abstract

Selecting the most appropriate protein sequences is critical for precision drug design. Here we describe Haplosaurus, a bioinformatic tool for computation of protein haplotypes. Haplosaurus computes protein haplotypes from pre-existing chromosomally-phased genomic variation data. Integration into the Ensembl resource provides rapid and detailed protein haplotypes retrieval. Using Haplosaurus, we build a database of unique protein haplotypes from the 1000 Genomes dataset reflecting real-world protein sequence variability and their prevalence. For one in seven genes, their most common protein haplotype differs from the reference sequence and a similar number differs on their most common haplotype between human populations. Three case studies show how knowledge of the range of commonly encountered protein forms predicted in populations leads to insights into therapeutic efficacy. Haplosaurus and its associated database is expected to find broad applications in many disciplines using protein sequences and particularly impactful for therapeutics design.

Duplication in ECR near HMX1 and a SNP in GATA6 Genes Regulate Microtia in Awassi Sheep

“…Our study did not find any significant mutations in exon 1 associated with ear size. Sequencing results showed a SNP intron 1 (23:34503270) on chromosome 23 [ 11 ]. Although exon 1 did not show any substantial mutations, a synonymous C to T mutation (locus 23:34502143) was found on exon 2 and a missense C to A mutation on exon 6 (23:34499639) [ 12 ].…”

Identification of Genome-Wide DNA Variants and SNP Haplotypes Associated with Avirulence Genes of Leptosphaeria Maculans in Western Canada

“…Furthermore, this study dealt with haploid L. maculans, and aimed at establishing most accurate association of avirulence/virulence with DNA mutations in Avr genes. Therefore, in this study all discovered SNPs were taken into account, even synonymous SNPs that could compromise protein functions to some extent [65]. This simplified SNP construction strategy can accommodate any SNPs, already-identified or newly-emerged in L.…”

“…Each SNP haplotype was given a name starting with the gene name (AvrLm1, AvrLm2, etc.) followed by "SNP_Haplo" plus a serial number; amino acid changes as the result of haplotypes, were referred to as protein haplotypes in a similar fashion [65], but with "SNP"…”

“…SNPs. It was believed that avirulence gene mutates in response to selection pressure imposed by resistant genes, so intuitively, Rlm4 and Rlm7, the cognate resistant genes corresponding to Synonymous polymorphisms in human could affect messenger RNA splicing, stability, and structure as well as protein folding[65], therefore, the SNPs in AvrLm3, either synonymous or non-synonymous, might change AvrLm3 protein transformation to avoid host recognition. On the other hand, varieties carrying Rlm4 and Rlm7 represented only about 2%, but AvrLm4-7 mutates more frequently than AvrLm2 and AvrLm3.…”

“…Ts/Tv is considered as an important parameter in evolutionary genetics[66]. Theoretically transversions are much less common than transition mutations, because the generation of transversions during replication requires much greater distortion of the double DNA helix than transition mutations[67], for this reason, nucleotide transitions are favored several fold over transversions, which was suggested to be a result of selection[65]. Relatively lower Ts/Tv ratios were reported in the ranges of 1.21 ~ 2.46 and 0.75 ~ 1.83 for some bacteria and unicellular eukaryotes respectively[68], but higher for fungi, for example, a ratio of 5 for rice blast fungus, Magnaporthe oryzae [69]; however, all these ratios were calculated at whole genome level.…”