The breakpoint process on RI chromosomes

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Presentation transcript:

The breakpoint process on RI chromosomes Karl W Broman Department of Biostatistics Johns Hopkins University http://www.biostat.jhsph.edu/~kbroman

C57BL/6

Recombinant inbred lines (by sibling mating)

Recombinant inbred lines (by selfing)

The “Collaborative Cross”

Genome of an 8-way RI

The goal Characterize the breakpoint process along a chromosome in 8-way RILs. Understand the two-point transition matrix. Study the clustering of the breakpoints, as a function of crossover interference in meiosis. Why? It’s interesting. Statistical analyses of such 8-way RIL data will require a model for this breakpoint process.

2 points in an RIL 1 2 r = recombination fraction = probability of a recombination in the interval in a random meiotic product. R = analogous thing for the RIL = probability of different genotypes at the two loci in a random RIL.

Haldane & Waddington 1931 Genetics 16:357-374

Equations for selfing

Recombinant inbred lines (by selfing)

Recombinant inbred lines (by sibling mating)

Equations for sib-mating

Result for sib-mating

Haldane & Waddington 1931 r = recombination fraction per meiosis between two loci Gi = allele at marker i in an RIL by sib-matings. Autosomes Pr(G1=A) = Pr(G1=B) = 1/2 Pr(G2=B | G1=A) = Pr(G2=A | G1=B) = 4r / (1+6r) X chromosome Pr(G1=A) = 2/3 Pr(G1=B) = 1/3 Pr(G2=B | G1=A) = 2r / (1+4r) Pr(G2=A | G1=B) = 4r / (1+4r) Pr(G2  G1) = (8/3) r / (1+4r)

8-way RILs Autosomes X chromosome Pr(G1 = i) = 1/8 Pr(G2 = j | G1 = i) = r / (1+6r) for i  j Pr(G2  G1) = 7r / (1+6r) X chromosome Pr(G1=A) = Pr(G1=B) = Pr(G1=E) = Pr(G1=F) =1/6 Pr(G1=C) = 1/3 Pr(G2=B | G1=A) = r / (1+4r) Pr(G2=C | G1=A) = 2r / (1+4r) Pr(G2=A | G1=C) = r / (1+4r) Pr(G2  G1) = (14/3) r / (1+4r)

The X chromosome

Computer simulations

3 points in an RIL 1 3 2 rij = recombination fraction for interval i,j Coincidence = Pr(rec’n in both intervals) / (r12 r23) = Pr(rec’n in 23 | rec’n in 12) / Pr(rec’n in 23) No interference  = 1 Positive interference  < 1 Negative interference  > 1 H&W result + map function  coincidence on a 2-way RIL chromosome This is actually included at the end of Haldane & Waddington (1931).

Coincidence No interference

Coincidence

Coincidence

Coincidence

Why the clustering of breakpoints? The really close breakpoints occur in different generations. Breakpoints in later generations can occur only in regions that are not yet fixed. The regions of heterozygosity are, of course, surrounded by breakpoints.

Summary RILs are useful. The Collaborative Cross could provide “one-stop shopping” for gene mapping in the mouse. Use of such 8-way RILs requires an understanding of the breakpoint process. We’ve extended Haldane & Waddington’s results to the case of 8-way RILs, but need to prove our results. We’ve shown clustering of breakpoints in RILs by sib-mating, even in the presence of strong crossover interference. Formulae for the 3-point problem in 8-way RILs still elude us. We’d like to: Fully characterize the breakpoint process. Study data (e.g., on 2-way RILs via selfing in Arabidopsis).