So far in this course we have dealt entirely with the evolution of characters that are controlled by simple Mendelian inheritance at a single locus. There are notes on the course website about gametic disequilibrium and how allele frequencies change at two loci simultaneously, but we didn’t discuss them. In every example we’ve considered we’ve imagined that we could understand something about evolution by examining the evolution of a single gene. That’s the domain of classical population genetics. For the next few weeks we’re going to be exploring a field that’s actually older than classical population genetics, although the approach we’ll be taking to it involves the use of population genetic machinery. If you know a little about the history of evolutionary biology, you may know that after the rediscovery of Mendel’s work in 1900 there was a heated debate between the “biometricians” (e.g., Galton and Pearson) and the “Mendelians” (e.g., de Vries, Correns, Bateson, and Morgan). Biometricians asserted that the really important variation in evolution didn’t follow Mendelian rules. Height, weight, skin color, and similar traits seemed to

Human biochemical genetics

The discovery of a series of genetic and serological markers associated with disease susceptibility and phenotype in inflammatory bowel disease has led to the prospect of an integrated classification system involving clinical, serological and genetic parameters. The Working Party has reviewed current clinical classification systems in Crohn's disease, ulcerative colitis and indeterminate colitis, and provided recommendations for clinical classification in practice. Progress with respect to integrating serological and genetic markers has been examined in detail, and the implications are discussed. While an integrated system is not proposed for clinical use at present, the introduction of a widely acceptable clinical subclassification is strongly advocated, which would allow detailed correlations among serotype, genotype and clinical phenotype to be examined and confirmed in independent cohorts of patients and, thereby, provide a vital foundation for future work.

/pdf/toward-an-integrated-clinical-molecular-and-serological-4qawah6knq.pdf

Toward an Integrated Clinical, Molecular and Serological Classification of Inflammatory Bowel Disease: Report of a Working Party of the 2005 Montreal World Congress of Gastroenterology

Few genetic markers, if any, have found such widespread use as microsatellites, or simple/short tandem repeats. Features such as hypervariability and ubiquitous occurrence explain their usefulness, but these features also pose several questions. For example, why are microsatellites so abundant, why are they so polymorphic and by what mechanism do they mutate? Most importantly, what governs the intricate balance between the frequent genesis and expansion of simple repetitive arrays, and the fact that microsatellite repeats rarely reach appreciable lengths? In other words, how do microsatellites evolve?

/pdf/microsatellites-simple-sequences-with-complex-evolution-5by92lfg3w.pdf

Microsatellites: simple sequences with complex evolution

An annotated reference sequence representing the hexaploid bread wheat genome in 21 pseudomolecules has been analyzed to identify the distribution and genomic context of coding and noncoding elements across the A, B, and D subgenomes. With an estimated coverage of 94% of the genome and containing 107,891 high-confidence gene models, this assembly enabled the discovery of tissue- and developmental stage-related coexpression networks by providing a transcriptome atlas representing major stages of wheat development. Dynamics of complex gene families involved in environmental adaptation and end-use quality were revealed at subgenome resolution and contextualized to known agronomic single-gene or quantitative trait loci. This community resource establishes the foundation for accelerating wheat research and application through improved understanding of wheat biology and genomics-assisted breeding.

Shifting the limits in wheat research and breeding using a fully annotated reference genome

By combining genome-wide association data from 8,130 individuals with type 2 diabetes (T2D) and 38,987 controls of European descent and following up previously unidentified meta-analysis signals in a further 34,412 cases and 59,925 controls, we identified 12 new T2D association signals with combined P<5x10(-8). These include a second independent signal at the KCNQ1 locus; the first report, to our knowledge, of an X-chromosomal association (near DUSP9); and a further instance of overlap between loci implicated in monogenic and multifactorial forms of diabetes (at HNF1A). The identified loci affect both beta-cell function and insulin action, and, overall, T2D association signals show evidence of enrichment for genes involved in cell cycle regulation. We also show that a high proportion of T2D susceptibility loci harbor independent association signals influencing apparently unrelated complex traits.

/pdf/twelve-type-2-diabetes-susceptibility-loci-identified-48vtfczwpg.pdf

Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis

https://www.stat.purdue.edu/~doerge/BIOINFORM.D/SPRING09/colin_MAGIC_COPB_2008.pdf

From mutations to MAGIC: resources for gene discovery, validation and delivery in crop plants.

https://www.cell.com/trends/plant-science/pdf/S1360-1385(06)00315-3.pdf

Methods for linkage disequilibrium mapping in crops.

Hitherto, we have treated dominance as a fixed property of the alleles concerned, both in cases where we were discussing dominance in fitness and in cases where we discussed dominance at the gross phenotypic level, as in the case of industrial melanism. However, there is much experimental evidence to indicate that the degree of dominance of one allele over another at a given locus (the “main” locus) can be affected by the presence or absence of specific alleles (“ modifiers of dominance”) at other loci. Ford (1940) showed that, in the currant moth, yellow wing ground colour could be made either near-dominant or near-recessive to white ground colour by selection of the appropriate genetic background. Fisher and Holt (1944) showed that, in the mouse, the mutant Danforth’s short tail, which normally shows marked expression in the heterozygote, could be made near-recessive, again by selection of the right genetic background. Ford (1955) showed that in the lesser yellow underwing moth, the near-dominance of dark to light in two widely separated natural populations depends on the presence of modifiers specific to the population from which moths were taken. Kettlewell (1965) showed that the dominance of dark to light in the peppered moth collapsed when the English background genotype was replaced with that from a Canadian stock. Clearly, modifiers of dominance are of widespread occurrence and, in some cases at least, are responsible for the presence of dominance as observed in nature.

Evolution of Dominance

Although commonplace in human disease genetics, genome-wide association (GWA) studies have only relatively recently been applied to plants. Using 32 phenotypes in the inbreeding crop barley, we report GWA mapping of 15 morphological traits across ∼500 cultivars genotyped with 1,536 SNPs. In contrast to the majority of human GWA studies, we observe high levels of linkage disequilibrium within and between chromosomes. Despite this, GWA analysis readily detected common alleles of high penetrance. To investigate the potential of combining GWA mapping with comparative analysis to resolve traits to candidate polymorphism level in unsequenced genomes, we fine-mapped a selected phenotype (anthocyanin pigmentation) within a 140-kb interval containing three genes. Of these, resequencing the putative anthocyanin pathway gene HvbHLH1 identified a deletion resulting in a premature stop codon upstream of the basic helix-loop-helix domain, which was diagnostic for lack of anthocyanin in our association and biparental mapping populations. The methodology described here is transferable to species with limited genomic resources, providing a paradigm for reducing the threshold of map-based cloning in unsequenced crops.

https://www.pnas.org/content/pnas/107/50/21611.full.pdf

Genome-wide association mapping to candidate polymorphism resolution in the unsequenced barley genome.

Congenital cataracts are an important cause of bilateral visual impairment in infants. In a four-generation family of English descent, we mapped dominant congenital posterior polar cataract to chromosome 11q22-q22.3. The maximum LOD score, 3.92 at recombination fraction 0, was obtained for marker D11S898, near the gene that encodes crystallin alpha-B protein (CRYAB). By sequencing the coding regions of CRYAB, we found in exon 3 a deletion mutation, 450delA, that is associated with cataract in this family. The mutation resulted in a frameshift in codon 150 and produced an aberrant protein consisting of 184 residues. This is the first report of a mutation, in this gene, resulting in isolated congenital cataract.

/pdf/alpha-b-crystallin-gene-cryab-mutation-causes-dominant-20175avh5m.pdf

Ian Mackay

Papers

From mutations to MAGIC: resources for gene discovery, validation and delivery in crop plants.

Methods for linkage disequilibrium mapping in crops.

Evolution of Dominance

Genome-wide association mapping to candidate polymorphism resolution in the unsequenced barley genome.

Alpha-b crystallin gene (CRYAB) mutation causes dominant congenital posterior polar cataract in humans