Haplotype phasing after joint estimation of recombination and linkage disequilibrium in breeding populations

Abstract

A novel method for haplotype phasing in families after joint estimation of recombination fraction and linkage disequilibrium is developed. Results from Monte Carlo computer simulations show that the newly developed E.M. algorithm is accurate if true recombination fraction is 0 even for single families of relatively small sizes. Estimates of recombination fraction and linkage disequilibrium were 0.00 (SD 0.00) and 0.19 (SD 0.03) for simulated recombination fraction and linkage disequilibrium of 0.00 and 0.20, respectively. A genome fragmentation phasing strategy was developed and used for phasing haplotypes in a sire and 36 progeny using the 50 k Illumina BeadChip by: a) estimation of the recombination fraction and LD in consecutive SNPs using family information, b) linkage analyses between fragments, c) phasing of haplotypes in parents and progeny and in following generations. Homozygous SNPs in progeny allowed determination of paternal fragment inheritance, and deduction of SNP sequence information of haplotypes from dams. The strategy also allowed detection of genotyping errors. A total of 613 recombination events were detected after linkage analysis was carried out between fragments. Hot and cold spots were identified at the individual (sire level). SNPs for which the sire and calf were heterozygotes became informative (over 90%) after the phasing of haplotypes. Average of regions of identity between half-sibs when comparing its maternal inherited haplotypes (with at least 20 SNP) in common was 0.11 with a maximum of 0.29 and a minimum of 0.05. A Monte-Carlo simulation of BTA1 with the same linkage disequilibrium structure and genetic linkage as the cattle family yielded a 99.98 and 99.94% of correct phases for informative SNPs in sire and calves, respectively.

Figure 1

Scheme of the genome fragmentation phasing strategy using SNP information from a sire and one progeny of cattle.

Figure 2

Three-dimensional plot of ln of the likelihood (equation A1) along recombination fraction (c) and linkage disequilibrium (δ) when testing a family of infinite size for different situations regarding c and δ. The allele frequencies were intermediate at the two loci. A) Situations simulated is c=0.20, δ=0. The maximum value was c=0.20, δ=0. B) Situations simulated is c=0.20, δ=0.20. The maximum value was at c=0.10, δ=0.15. C) Situations simulated is c=0.00, δ=0.00. The maximum value was c=0.00, δ=0.00. D) Situations simulated is c=0.00, δ=0.20. The maximum value was c=0.00, δ=0.20.

Figure 3

Genome-wide estimates of the recombination fraction between consecutive SNP during fragmentation along physical distance for the 29 autosomal chromosomes.

Figure 4

Histograms of the number of fragments for the 29 autosomal chromosomes according to fragment’s size (number of SNPs).

Figure 5

Histograms of the number of fragments for the autosomal chromosomes that have 200 or more SNPs (cold spots) per fragment for autosomes 1,3,4,11,13,16,17,20, and 21.

Figure 6

Distribution of the number of recombination events for the 36 calves in a half-sib family.

Figure 7

Estimates of recombination fraction between fragments across the 29 autosomal chromosomes.

Figure 8

Paternal versus maternal ROIs for all combinations of a pair of half-sibs. There were 36 calves which makes 630 combinations (points in the graph).

Figure 9

Histograms of the distribution of fragments that are ROIs for any pair of individuals and with size larger than 10 Mb. The histogram represents the distribution of ROIs of origin paternal (left) and maternal (right).