Academic journal article Genetics

Tilting at Quixotic Trait Loci (QTL): An Evolutionary Perspective on Genetic Causation

Academic journal article Genetics

Tilting at Quixotic Trait Loci (QTL): An Evolutionary Perspective on Genetic Causation

Article excerpt

ABSTRACT

Recent years have seen great advances in generating and analyzing data to identify the genetic architecture of biological traits. Human disease has understandably received intense research focus, and the genes responsible for most Mendelian diseases have successfully been identified. However, the same advances have shown a consistent if less satisfying pattern, in which complex traits are affected by variation in large numbers of genes, most of which have individually minor or statistically elusive effects, leaving the bulk of genetic etiology unaccounted for. This pattern applies to diverse and unrelated traits, not just disease, in basically all species, and is consistent with evolutionary expectations, raising challenging questions about the best way to approach and understand biological complexity.

THE past 25 years have seen an outpouring of new knowledge in genetics on a scale unprecedented in the history of any science. For important societal reasons the heaviest research investment has been in the genetics of human disease, but there has been comparable progress in understanding normal and abnormal traits in humans andmany other species.Numerous approaches, that I generically refer to as "mapping," have been developed to find statistical association between phenotypes and genotypes. They include searching variation in known candidate genes, genomewide linkage studies in samples of relatives, andgenomewide association studies in population samples such as comparing cases and controls (e.g., Terwilliger and Goring 2000; Mackay 2001; Rao and Province 2001; Georges 2007; Rao 2008).

The objective of mapping is reductionistic: to dissect biological traits into enumerable genotypes with estimable effects. Complexity is not a precise concept, but generally means that many genes as well as environmental factors produce a trait, with different combinations of these factors accounting for its variation. Causation is often expressed as probabilistic risk or penetrance, the probability that someone with a given genotype will manifest a particular trait. Whether risk is probabilistic because of the nature of sampling, unmeasured heterogeneity, or because of inherently probabilistic processes is usually not known. Causation takes two faces: to describe the basis of variation of the trait in populations and to identify the origin of the trait's value in a specific individual. These are philosophically related, but different in practical terms.

Complex phenotypes can usually be viewed in quantitative terms. A trait may be defined quantitatively, like blood pressure, or may be viewed as the qualitative outcome of underlying quantitative risk factors crossing some threshold, as hypertension relative to blood pressure. The quantitative effect may pertain to onset age, severity, or the probability of a stochastic event such as of stroke as a function of blood pressure.

For decades in the history of modern genetics there were few systematic ways to go beyond segregation analysis, a statistical method for testing whether trait variation that clusters in families is consistent with the inherently probabilistic process of Mendelian inheritance. Only in fortuitous exceptions could a specific protein or chromosome anomaly be associated with a disease. Laborious mapping based on recombination among Mendelian traits was possible in experimental plants or animals, but genes and even their number remained largely unidentified until surprisingly recently.

A chromosomal region or gene identified by statistical association can for purposes here be generically referred to as a quantitative trait locus (QTL). The major breakthrough was the advent, just a generation ago, of systematic genomewide mapping techniques that, quite remarkably, could identify QTL without our having to know the biological nature of a trait so long as it could be defined and measured, an advance properly characterized as "a new horizon in human genetics" (BOTSTEIN et al. …

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