Weekly Bulletin

Autism, now called "Autism Spectrum Disorder" (ASD), is a neuro-developmental condition that is diagnosed in early childhood.It is heavily gender-biased as it affects by today's criteria about 1% of boys and 1/4% of girls. It also has a strong genetic basis as evidenced by studies of identical twins. Unfortunately, what we have learned today is discouraging: The number of genes causally related to ASD is in the hundreds, of which about 150 have been identified, each accounting for only a tiny fraction of ASD variability. While the search for causally linked genes is ongoing, we also have to ask more global questions: How can we think about the relative protection from ASD enjoyed by females? How can the gender bias be reconciled with known inheritance mechanisms? To answer such questions, Wigler et al. (2007) proposed a "Unified Theory" according to which females are the stores of damaging genetic variants for which they have relative protection, but cause ASD in their sons who lack this protection. To capture Wigler et al.'s theory and combine it with today's knowledge of the "polygenic" nature of ASD, we developed a scatter shot model of "damaging alleles" which have "lower penetrance" in females than males. In this model we are able to match the known "prevalences" of 1% in boys and 1/4% in girls, as well as other known global features such as the existence of high risk families. Most importantly, we are able to prove mathematically a prediction of Wigler et al.s' theory: genetic sharing among autistic male siblings is greater with the mother than the father. Surprisingly, the latest empirical evidence from Wigler's lab seems to indicate that genetic sharing among autistic male siblings is greater with the father than the mother. If this evidence can be firmed up, it refutes the Unified Theory and requires new ideas. One such idea involves the existence of "protecting alleles", which we are currently incorporating in our model.