A rigorous measure of genome-wide genetic shuffling that takes into account crossover positions and Mendel’s second law
Proceedings of the National Academy of Sciences, 116 (5):
1659--1668 (2019)DOI: 10.1073/pnas.1817482116
Abstract
An important process in sexual organisms is the shuffling of maternal and paternal DNA in gametes by both crossing over and independent assortment of homologous chromosomes. Traditional measures of the total amount of genetic shuffling simply count the average number of crossovers, failing to take into account independent assortment and, importantly, the positions of crossovers. We develop a measure of total shuffling that takes into account these features: r¯, the probability that a randomly chosen pair of loci shuffles their alleles in a gamete. Measuring r¯ in humans, we find that total shuffling is close to its maximum possible value of one-half and that this high value is largely due to independent assortment.Comparative studies in evolutionary genetics rely critically on evaluation of the total amount of genetic shuffling that occurs during gamete production. Such studies have been hampered by the absence of a direct measure of this quantity. Existing measures consider crossing-over by simply counting the average number of crossovers per meiosis. This is qualitatively inadequate, because the positions of crossovers along a chromosome are also critical: a crossover toward the middle of a chromosome causes more shuffling than a crossover toward the tip. Moreover, traditional measures fail to consider shuffling from independent assortment of homologous chromosomes (Mendel’s second law). Here, we present a rigorous measure of genome-wide shuffling that does not suffer from these limitations. We define the parameter r¯ as the probability that the alleles at two randomly chosen loci are shuffled during gamete production. This measure can be decomposed into separate contributions from crossover number and position and from independent assortment. Intrinsic implications of this metric include the fact that r¯ is larger when crossovers are more evenly spaced, which suggests a selective advantage of crossover interference. Utilization of r¯ is enabled by powerful emergent methods for determining crossover positions either cytologically or by DNA sequencing. Application of our analysis to such data from human male and female reveals that (i) r¯ in humans is close to its maximum possible value of 1/2 and that (ii) this high level of shuffling is due almost entirely to independent assortment, the contribution of which is \~30 times greater than that of crossovers.