Psychiatric Genetics Mapping Genotype to Phenotype

This months Public Library of Science Biology Journal features an interesting essay by Kevin J. Mitchell, tying together the fields of neurodevelopment, epigenetics and genetics.

What makes some people neurotic or schizophrenic or right-handed or fearless? Are these behavioural differences caused by literal differences in how individuals’ brains are wired? If so, what causes those differences?

This age-old question of nature versus nurture can be recast in more realistic terms based on our modern understanding of genetics, development, and neuroscience. The challenge in this area is to understand how genotype is mapped to phenotype, not just in terms of the average effects of single genes across populations but also in terms of their combined effects in shaping the phenotypes of individuals.

In genetics, genotype is the part of an person’s genes which contributes to determining a particluar trait , while phenotype refers to the actual manifestation of a trait, such as size, eye color, or handedness of an individual.

Why do some identical twins behave differently from each other? Obviously, environmental factors (nurture) play a role, but psychiatric geneticists see a deeper level of complexity:

Monozygotic twins in humans, and genetically identical organisms in other species, show considerable phenotypic variability. This phenotypic variability can be continuous or dichotomous and is observed for behavioural traits and psychiatric disorders and also for anatomical phenotypes including neuronal connectivity. This is true even in animal studies where the external environment and even the intra-uterine environment have been controlled as carefully as possible, suggesting an intrinsic source of variability.

The Epigenetic Landscape

To explain this variability, epigenetic differences have been proposed as one mechanism. Epigenetics is the study of methods of biological inheritance which do not directly relate to the inheritance of collections of genes, and also to reversible, heritable changes in gene regulation that occur without a change in genotype.

Waddington’s “epigenetic landscape”  provides an elegant illustration of the nonlinear relationship between genotype and phenotype. An organism, represented by a ball, moves through developmental time over an undulating landscape with a number of valleys representing potential phenotypic end points.

The shape of this epigenetic landscape is determined by the organism’s genotype, with the effects of individual genes (or combinations of genes) acting to increase or decrease the likelihood of passage into any particular valley. While these genotypic effects (importantly including sex effects) determine the probability of various phenotypes, the precise phenotype that actually emerges in an individual is also influenced by small random variation at any of a number of developmental “choice points” that can push an organism into a particular phenotypic valley, from which it becomes increasingly difficult to emerge. Environmental perturbations at these critical stages can have similar effects, depending on the underlying susceptibility to them (modelling gene environment interactions)

The test for neurodevelopmental and psychiatric geneticists is to develop techniques that take all these aspects into consideration in their attempts to map from genotype to anatomical and physiological phenotypes and further to behavioral and cognitive traits. Whichever approaches are taken, researchers have begun to understand that to grasp psychological traits origins, they need to keep sight of the trajectories of neurological development, in addition to the resulting individual traits.