The August 7 issue of Science includes a report on quantitative trait loci (QTLs) affecting flowering time in maize. It is important because it presents the first results with an important new technique known as nested association mapping (NAM), which utilizes a large set of recombinant inbred lines derived from diverse founder lines. The article is accompanied by an excellent piece by Trudy Mackay that puts this method into perspective. "Linkage mapping can readily detectchromosomal regions containing one or more QTLs that affecta trait ... but it is difficult to precisely localize the QTLs. This approach usually relies on crosses between two strains,thus capturing only a tiny fraction of genetic diversity inthe population. By contrast, association mapping widely samplesgenetic diversity and requires fewer individuals, but hasless power to detect QTLs when alleles are not common." The new method combines advantages of these earlier approaches. It also provides surprising results, different from what has been found in other systems. In particular, the authors find numerous genes of small effect with few genetic or environmental interactions, so that "a simple additive model accurately predicts flowering time for maize." The authors argue that their data supports "common genes with uncommon variants." Moving forward, I look forward to seeing this system applied to other traits, and to the discovery of specific genes involved in this and other traits.
McMullenetal.. 2009 "Genetic Properties of the Maize Nested Association Mapping Population" Science 325: 737. This is the main paper presented here. It describes QTLs for flowering time.
Mackay. 2009 "A-maize-ing Diversity" Science 325: 688. A very nice summary of how NAM compares to other methods for finding QTLs and how these results compare with those from other systems.
Mackay. 2001. "The genetic architecture of quantitative traits." Annu. Rev. Genet.35: 303.
Yuetal. "Genetic Design and Statistical Power of Nested Association Mapping in Maize" Genetics 178: 539. An earlier paper from some of the same authors describing the NAM method.
I have been fascinated by microexons for a long time. Many exons are relatively small (less than 100 bp.), but still large enough for recognition of the two splice sites by the splicing machinery simultaneously. In fact, the boundaries of such exons are often recognized coordinately in a process known as exon definition. Introns that are too small for that, so that the two splice sites cannot be recognized simultaneously, are termed microexons. Many are less than 10 nucleotides (see Volfovsky et al. 2003). Sometimes the downstream intron must be removed first (e.g. potato invertase). The inability of the splicing machinery to recognize both splice sites simultaneously due to physical occlusion probably comes into play with exons less than about 30 nucleotides. Although the exact length at which this occurs is difficult to know for sure (especially in a species like S. mansoni, for which we have little experimental data, it is nevertheless what I consider to be the defining characteristic of a true microexon. Microexons are characterized by alternative splicing and annotation errors.
Now, the genome of the blood fluke Schistosoma mansoni reveals "at least 45 genes with an unusual microexon structure," such that microexons make up the majority of the coding sequence in those genes. As is often true with microexons, these genes are alternatively spliced, suggesting that a "'pick and mix' strategy is used to create protein variation." These MEGs, or microexon genes, have the hallmarks of secreted proteins and are expressed in the intramammalian stages of the life cycle. It will be interesting to see what role microexon splicing or these genes turns out to play.
A Science News Focus piece by Don Monroe ("Genomic Clues to DNA Treasure Sometimes Lead Nowhere") presents the concerns that "not all conserved sequences are important and, worse, that not all important sequences are conserved." While I think that formulation is a bit misleading, it does point to some very interesting and timely questions in genomics. Eddie Rubin and colleagues have shown that "deletion of ultraconserved sequences yields viable mice" (PLOS Biology 2007). While this is not the same as showing that the sequences are not important, it does point to an important specific question ("What are these noncoding ultraconserved sequences in vertebrate genomes doing?") and an important general question ("Why is the correlation between gene importance and gene evolutionary rate so weak?" Wang and Zhang 2009). The article got me thinking about those questions.
However, the conservation of nonessential sequences is not new, and there are several well-established means by which the loss of sequences important enough to be maintained by purifying selection can fail to produce a phenotype. First, the specific sequences tested can be redundant. Second, the process under selection can be important without being essential. Examples of widely conserved processes that are not essential in all species include telomerase and nonsense-mediated decay. Third, the selection can be imposed by something (such as a rare pathogen) that does not arise in the experimental system. However unlikely these cases may seem, I know of no means other than purifying selection by which a sequence can be maintained unchanged for millions of years.