Human Genetics and Clinical Aspects of Neurodevelopmental Disorders

Human Genetics and Clinical Aspects of Neurodevelopmental Disorders

The Reddit AMA of Weiss and Buchanan is full of many interesting comments and discussions. The highest rating of the following question suggests that people are coming to realize that the scientists over- sold and over-hyped what could be achieved through the human genome sequencing project.

Why hasn’t genetics led to the groundbreaking cures initially promised?

mermaidstale: Basically, because the diseases that most of us will get as we age turn out to be more complex than people had thought. I think we can blame the idea that we will find genes ‘for’ these kinds of diseases on Mendel, whose work with traits in peas led people to think that most traits were going to behave in the same predictable way that wrinkled, or yellow, or green peas do. Instead, it is turning out that there are many pathways to most traits, usually including many genes and environmental factors as well. So, diseases won’t be as predictable as we’ve been promised, because everyone’s genome is different, and environmental risk factors are hard to identify (is butter good or bad for us?), and future environments impossible to predict.

In this context, Gholson Lyon pointed out that he wrote a book chapter that the readers will find useful. The article is well-researched, well-written and is available open-access from biorxiv.

There are ~12 billion nucleotides in every cell of the human body, and there are ~25-100 trillion cells in each human body. Given somatic mosaicism, epigenetic changes and environmental differences, no two human beings are the same, particularly as there are only ~7 billion people on the planet. One of the next great challenges for studying human genetics will be to acknowledge and embrace complexity. Every human is unique, and the study of human disease phenotypes (and phenotypes in general) will be greatly enriched by moving from a deterministic to a more stochastic/probabilistic model. The dichotomous distinction between simple and complex diseases is completely artificial, and we argue instead for a model that considers a spectrum of diseases that are variably manifesting in each person. The rapid adoption of whole genome sequencing (WGS) and the Internet-mediated networking of people promise to yield more insight into this century-old debate. Comprehensive ancestry tracking and detailed family history data, when combined with WGS or at least cascade-carrier screening, might eventually facilitate a degree of genetic prediction for some diseases in the context of their familial and ancestral etiologies. However, it is important to remain humble, as our current state of knowledge is not yet sufficient, and in principle, any number of nucleotides in the genome, if mutated or modified in a certain way and at a certain time and place, might influence some phenotype during embryogenesis or postnatal life.

Written by M. //