Rosa Tarrío

A methodological bias toward overestimation of molecular evolutionary time scales

There is presently a conflict between fossil- and molecular-based evolutionary time scales. Molecular approaches for dating the branches of the tree of life frequently lead to substantially deeper times of divergence than those inferred by paleontologists. The discrepancy between molecular and fossil estimates persists despite the booming growth of sequence data sets, which increasingly feeds the interpretation that molecular estimates are older than stratigraphic dates because of deficiencies in the fossil record. Here we show that molecular time estimates suffer from a methodological handicap, namely that they are asymmetrically bounded random variables, constrained by a nonelastic boundary at the lower end, but not at the higher end of the distribution. This introduces a bias toward an overestimation of time since divergence, which becomes greater as the length of the molecular sequence and the rate of evolution decrease.

Convergent neofunctionalization by positive Darwinian selection after ancient recurrent duplications of the xanthine dehydrogenase gene

Gene duplication is a primary source of molecular substrate for the emergence of evolutionary novelties. The chances for redundant gene sequences to evolve new functions are small compared with the probability that the copies become disabled by deleterious mutations. Functional divergence after gene duplication can result in two alternative evolutionary fates: one copy acquires a novel function (neofunctionalization), or each copy adopts part of the tasks of their parental gene (subfunctionalization). The relative prevalence of each outcome is unknown. Similarly unknown is the relative importance of positive selection versus random fixation of neutral mutations. Aldehyde oxidase (Ao) and xanthine dehydrogenase (Xdh) genes encode two complex members of the xanthine oxidase family of molybdo-flavoenzymes that carry different functions. Ao is known to have originated from a duplicate of an Xdh gene in eukaryotes, before the origin of multicellularity. We show that (i) Ao evolved independently twice from two different Xdh paralogs, the second time in the chordates, before the diversification of vertebrates; (ii) after each duplication, the Ao duplicate underwent a period of rapid evolution during which identical sites across the two molecules, involving the flavin adenine dinucleotide and substrate-binding pockets, were subjected to intense positive Darwinian selection; and (iii) the second Ao gene likely endured two periods of redundancy, initially as a duplicate of Xdh and later as a functional equivalent of the old Ao, which is currently absent from the vertebrate genome. Caution is appropriate in structural genomics when using sequence similarity for assigning protein function.

Erratic overdispersion of three molecular clocks: GPDH, SOD, and XDH

The neutrality theory predicts that the rate of neutral molecular evolution is constant over time, and thus that there is a molecular clock for timing evolutionary events. It has been observed that the variance of the rate of evolution is generally larger than expected according to the neutrality theory, which has raised the question of how reliable the molecular clock is or, indeed, whether there is a molecular clock at all. We have carried out an extensive investigation of three proteins, glycerol-3-phosphate dehydrogenase (GPDH), superoxide dismutase (SOD), and xanthine dehydrogenase (XDH). We have observed that (i) the three proteins evolve erratically through time and across lineages and (ii) the erratic patterns of acceleration and deceleration differ from locus to locus, so that one locus may evolve faster in one than another lineage, whereas the opposite may be the case for another locus. The observations are inconsistent with the predictions made by various subsidiary hypotheses proposed to account for the overdispersion of the molecular clock.

A novel MYH7 mutation links congenital fiber type disproportion and myosin storage myopathy

This study aimed to identify the genetic defect in a multigenerational family presenting an autosomal dominant myopathy with histological features of congenital fiber type disproportion. Linkage analysis and genetic sequencing identified, in all affected members of the family, the c.5807A>G heterozygous mutation in MYH7, which encodes the slow/β-cardiac myosin heavy chain. This mutation causes skeletal but not cardiac involvement. Myosin heavy chain expression pattern was also characterized by immunohistochemistry, western blot and q-PCR in muscle biopsies from two patients aged 25 and 62, respectively. While only congenital fiber type disproportion was observed in the younger patient, older patients biopsy presented aggregates of slow myosin heavy chains, in fiber sub-sarcolemmal region. These clinico-pathologic findings suggest a novel phenotype within the emerging group of hereditary myosin myopathies, which in this family presents typical characteristics of congenital fiber type disproportion in early stages and later evolves to myosin storage myopathy.

A new Drosophila spliceosomal intron position is common in plants

The 25-year-old debate about the origin of introns between proponents of “introns early” and “introns late” has yielded significant advances, yet important questions remain to be ascertained. One question concerns the density of introns in the last common ancestor of the three multicellular kingdoms. Approaches to this issue thus far have relied on counts of the numbers of identical intron positions across present-day taxa on the assumption that the introns at those sites are orthologous. However, dismissing parallel intron gain for those sites may be unwarranted, because various factors can potentially constrain the site of intron insertion. Demonstrating parallel intron gain is severely handicapped, because intron sequences often evolve exceedingly fast and intron phylogenetic distributions are usually ambiguous, such that alternative loss and gain scenarios cannot be clearly distinguished. We have identified an intron position that was gained independently in animals and plants in the xanthine dehydrogenase gene. The extremely disjointed phylogenetic distribution of the intron argues strongly for separate gain rather than recurrent loss. If the observed phylogenetic pattern had resulted from recurrent loss, all observational support previously gathered for the introns-late theory of intron origins based on the phylogenetic distribution of introns would be invalidated.

'Costa da Morte' ataxia is spinocerebellar ataxia 36: clinical and genetic characterization

Spinocerebellar ataxia 36 has been recently described in Japanese families as a new type of spinocerebellar ataxia with motor neuron signs. It is caused by a GGCCTG repeat expansion in intron 1 of NOP56. Family interview and document research allowed us to reconstruct two extensive, multigenerational kindreds stemming from the same village (Costa da Morte in Galicia, Spain), in the 17th century. We found the presence of the spinocerebellar ataxia 36 mutation co-segregating with disease in these families in whom we had previously identified an ∼0.8 Mb linkage region to chromosome 20 p. Subsequent screening revealed the NOP56 expansion in eight additional Galician ataxia kindreds. While normal alleles contain 5–14 hexanucleotide repeats, expanded alleles range from ∼650 to 2500 repeats, within a shared haplotype. Further expansion of repeat size was frequent, especially upon paternal transmission, while instances of allele contraction were observed in maternal transmissions. We found a total of 63 individuals carrying the mutation, 44 of whom were confirmed to be clinically affected; over 400 people are at risk. We describe here the detailed clinical picture, consisting of a late-onset, slowly progressive cerebellar syndrome with variable eye movement abnormalities and sensorineural hearing loss. There were signs of denervation in the tongue, as well as mild pyramidal signs, but otherwise no signs of classical amyotrophic lateral sclerosis. Magnetic resonance imaging findings were consistent with the clinical course, showing atrophy of the cerebellar vermis in initial stages, later evolving to a pattern of olivo-ponto-cerebellar atrophy. We estimated the origin of the founder mutation in Galicia to have occurred ∼1275 years ago. Out of 160 Galician families with spinocerebellar ataxia, 10 (6.3%) were found to have spinocerebellar ataxia 36, while 15 (9.4%) showed other of the routinely tested dominant spinocerebellar ataxia types. Spinocerebellar ataxia 36 is thus, so far, the most frequent dominant spinocerebellar ataxia in this region, which may have implications for American countries associated with traditional Spanish emigration.

Colorectal Cancer Susceptibility Quantitative Trait Loci in Mice as a Novel Approach to Detect Low-Penetrance Variants in Humans: A Two-Stage Case-Control Study

Thirty-five percent of colorectal cancer (CRC) susceptibility is thought to be attributable to genetics, but only a small proportion of the cases (<6%) can be explained by highly penetrant mutations. The rest of the susceptibility could be explained by a number of low-penetrance variants following a polygenic model of inheritance. Genetic modeling in rodents has been a successful tool for the unraveling of the genetic basis of diseases. The investigation of mouse quantitative trait loci led to the discovery of 15 “susceptibility to colorectal cancer” (Scc) loci. Thus, we aimed to analyze the human-mouse syntenic regions defined by these Scc loci and select human candidate genes within. Twenty-one genes were chosen and their single-nucleotide polymorphisms were tested as possible low-penetrance variants predisposing to CRC risk. Our most strongly associated single-nucleotide polymorphism, rs954353, seems to be in the 5′ region of the CYR61 gene, which could implicate it in terms of the cis-regulation of the gene. CYR61 has been proposed as a connection point among signaling pathways and a probable marker for early CRC detection. However, we could not replicate the association. Despite our negative results, we believe that our candidate gene selection strategy could be quite useful in the future determination of variants predisposing to disease. Cancer Epidemiol Biomarkers Prev; 19(2); 619–23