The Linkage Disequilibrium (LD) of unlinked loci can be used to estimate contemporary effective population size (Ne) of one to a few generations ago. In genomic datasets loci on different chromosomes are considered unlinked, but there are many more pairs of unlinked loci than there are independent pairs of chromosomes, resulting to confidence intervals (C.I.) being too narrow if the non-independence is not taken into account. Simulations were run to investigate the correlation structure among LD of unlinked loci, which can be expressed by the LD of loci along the same chromosomes, based on a discovery of a novel Random Probe LD estimator. We classify the correlation into two categories: overlapping of loci and disjoint pairs. The former is induced from the same locus being considered twice and is the stronger form of correlation. These correlations feed into ρ, a parameter to quantify the degree of pseudo-replication in a dataset, and further a correction formula from which C.I. can be properly inferred. We demonstrate the use of our method via an analysis of genomic data from the malaria-transmitting Anopheles gambiae s.s mosquitoes. Apart from the point and C.I. estimates, we find that is inflated by about 550 times due to pseudo-replication, highlighting the danger of not handling genetic correlation properly.
Tin-Yu J. Hui, Lai-Yin Zhou, A. Burt· bioRxiv· 0 citations
Insecticide resistance in mosquito vectors and antimalarial drug resistance in parasites threaten progress towards malaria elimination, prompting the development of alternative control strategies such as CRISPR-Cas9 gene drives. The sex determination gene femaleless (fle, AGAP013051), which is required for female development in Anopheles gambiae, is a promising target for population-suppression approaches aimed at disrupting female-specific genes that affect fertility or viability. However, its functions beyond sex determination remain unknown. Here, we engineered homing gene drives targeting fle and employed germline promoters with distinct temporal expression profiles, early-acting zero population growth (zpg, AGAP006241) and late-acting sporulation defective 11 (spo11, AGAP010898), to modulate Cas9 activity. The zpg-driven system achieved up to 98% transmission through males but caused complete sterility in hemizygous females due to early biallelic disruption of fle during germline development. Delaying cas9 expression with the spo11 promoter partially restored female fertility, although female transmission remained close to Mendelian levels (59%). These results reveal an essential role for fle in female gametogenesis in addition to its established function in sex determination. Population modelling predicts that releasing zpg-drive males at 16.9% of the wild-type male population could reduce female abundance by 95% within 36 generations. Collectively, our findings reveal a previously unrecognised reproductive function of fle that limits gene-drive spread and provide important insights for the design of vector-control strategies targeting genes with essential germline functions.
B. Fasulo, W. Garrood, J. Philpott et al.· bioRxiv· 0 citations
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