Accumulation And Functional Architecture Of Deleterious Genetic Variants During The Extinction Of Wrangel Island Mammoths

Woolly mammoths were among the most abundant cold adapted species during the Pleistocene. Their once large populations went extinct in two waves, an end-Pleistocene extinction of continental populations followed by the mid-Holocene extinction of relict populations on St. Paul Island ~5,600 years ago and Wrangel Island ~4,000 years ago. Population and conservation genetics theory predicts that deleterious alleles will accumulate as populations decline, leading to downward spiral of declining population size and fitness ending in extinction (mutational meltdown). While the extinction of Wrangel Island mammoths was preceded by prolonged demographic decline, reduced population size and genetic diversity, recurrent inbreeding, and the fixation of deleterious alleles, the functional consequences of these processes are unclear. Here we show that the extinction of Wrangel Island mammoths was accompanied by an accumulation of deleterious mutations that are predicted to cause diverse behavioral and developmental defects. Resurrecting and functional characterization of Wrangel Island mammoth genes with putative deleterious substitutions identified both loss and gain of function mutations associated with ciliopathies, oligozoospermia and reduced fertility, and neonatal diabetes. These results indicate that last mammoths likely suffered from genetic disease that reduced fitness and directly contributed to their extinction.