Topic: whole-genome sequencing

This lecture reviews genetic explanations for single-gene disorders through Mendelian inheritance and examples such as achondroplasia. Whole-genome sequencing helps identify causal variants, while comparisons of rare and common mutations illuminate disease mechanisms. The discussion also considers what transcriptomic and proteomic measurements add to clinical genetic investigation.

The human fetal brain shows extensive somatic mosaicism with each embryonic neuronal progenitor cell (NPC) accumulating five mutations daily, whereas postnatal mature neurons accumulate 23 mutations yearly. Somatic mosaicism can contribute to neurodevelopmental disorders like schizophrenia and play a role in interindividual phenotypic differences. Rapid NPC proliferation may cause the high mutation rate, and somatic mutations can alter NPC survival, proliferation, or differentiation, causing clonal selection. Little is known about the mechanisms driving clonal evolution in neurotypical brains