The relationship between genotype and phenotype has, at its core, a premise that associated genetic variation is exerting a functional consequence. In mendelian traits, high penetrance, typically rare, alleles have been identified that result in often dramatic effects for the encoded protein or regulation of gene expression. This relationship is not necessarily clear cut and while major effects are seen involving a particular gene, often variation in modifier genes may play a role in the observed pheno-typic diversity, as seen for example in the iron storage disorder haemochromatosis. The situation becomes even harder to dissect in common multifactorial traits where, typically, fine mapping is difficult and defining specific causative functional variants is even harder.
The functional consequences of genetic variation are diverse and complex, as illustrated in Chapter 1 for the globin locus and elsewhere in this volume. Effects involving modulation of the structure or function of the encoded protein range from amino acid substitutions and truncation of the length of the polypeptide chain, to diverse and complex effects on the regulation of splicing. The control of gene expression has also been shown to be regulated to varying extents by genetic variation including gene dosage effects associated with copy number variation as well as effects for example on local and distant regulatory elements associated with sequence level diversity, modulating recruitment of specific transcription factors and even resulting in the creation of a novel gene promoter (Section 1.3.9).
How to define functionally important genetic variation remains a major challenge and significant roadblock in the field. Advances in structural biology and knowledge of the underlying biology of transcription and translation are significantly advancing our ability to predict and test the consequences of coding and other variants for protein structure and function. The nature and complexity of the biology underlying alternative splicing is also being increasingly appreciated and the sophistication of approaches to understand the consequences of genetic diversity for splicing are rapidly increasing. Such knowledge is also critical to the analysis of gene expression with recent advances in mapping genetic determinants of expression quantitative traits needing to include the diversity in alternative spliced transcript isoforms in any analysis (Section 11.6). Mapping quantitative trait loci (QTLs) using the 'genetical genomics' approach looks set to be a very powerful approach. Exciting data are now available from model organisms, as well as human cell lines and increasingly from primary human cells and tissues (Section 11.3).
In trying to define the functional consequences of genetic diversity for gene expression, ongoing work to understand the control of this complex process has been essential and will continue to be so, with fundamental insights from international collaborative studies such as the ENCODE Project (Birney et al. 2007). Transcriptional regulation is a multilayered and intricate process which genetic variation may modulate at many different points, ranging from promoter function to disruption of enhancer elements. Through using bioinformatic approaches and wet lab experiments at the bench, our ability to investigate and test such effects continues to develop. However, many current approaches remain technically demanding and not amenable to high throughput analysis making further methodological advances in this area a continued priority.
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