Biology subjects

Kamath, A.

Publications and source records attributed to Kamath, A..

3 recordsLinked to original sources

bioRxiv2018

ITPase Deficiency Causes Martsolf Syndrome With a Lethal Infantile Dilated Cardiomyopathy

Martsolf syndrome is characterized by congenital cataracts, postnatal microcephaly, developmental delay, hypotonia, short stature and biallelic hypomorphic mutations in either RAB3GAP1 or RAB3GAP2. Through genetic analysis of 85 unrelated \"mutation negative\" probands referred with Martsolf syndrome we identified two individuals with different homozygous null mutations in ITPA, the gene encoding inosine triphosphate pyrophosphatase (ITPase). The probands reported here each presented with a lethal and highly distinctive disorder; Martsolf syndrome with infantile-onset dilated cardiomyopathy. Severe ITPase-deficiency has been previously reported with infantile epileptic encephalopathy (MIM 616647). ITPase acts to prevent incorporation of inosine bases (rl/dl) into RNA and DNA. In Itpa-null cells, dI was undetectable in genomic DNA. dI could be identified at a low level in mtDNA but this was not associated with detectable mitochondrial genome instability, mtDNA depletion or biochemical dysfunction of the mitochondria. rI accumulation was detectable in lymphoblastoid RNA from an affected individual. In Itpa-null mouse embryos rI was detectable in the brain and kidney with the highest level seen in the embryonic heart (rI at 1 in 385 bases). Transcriptome and proteome analysis in mutant cells revealed no major differences with controls. The rate of transcription and the total amount of cellular RNA also appeared normal. rI accumulation in RNA - and by implication rI production - correlates with the severity of organ dysfunction in ITPase deficiency but the basis of the cellulopathy remains cryptic. While we cannot exclude cumulative minor effects, there are no major anomalies in the production, processing, stability and/or translation of mRNA.\n\nAuthor SummaryNucleotide triphosphate bases containing inosine, ITP and dITP, are continually produced within the cell as a consequence of various essential biosynthetic reactions. The enzyme inosine triphosphate pyrophosphatase (ITPase) scavenges ITP and dITP to prevent their incorporation into RNA and DNA. Here we describe two unrelated families with complete loss of ITPase function as a consequence of disruptive mutations affecting both alleles of ITPA, the gene that encodes this protein. Both of the families have a very distinctive and severe combination of clinical problems, most notably a failure of heart muscle that was lethal in infancy or early childhood. They also have features of another rare genetic disorder affecting the brain and the eyes called Martsolf syndrome. We could not detect any evidence of dITP accumulation in genomic DNA from the affected individuals. A low but detectable level of inosine was present in the mitochondrial DNA but this did not have any obvious detrimental effect. The inosine accumulation in RNA was detectable in the patient cells. We made both cellular and animal models that were completely deficient in ITPase. Using these reagents we could show that the highest level of inosine accumulation into RNA was seen in the embryonic mouse heart. In this tissue more than 1 in 400 bases in all RNA in the cell was inosine. In normal tissues inosine is almost undetectable using very sensitive assays. The inosine accumulation did not seem to be having a global effect on the balance of RNA molecules or proteins.

genetics↗

bioRxiv2017

Integrating movement behavior with sexual selection in the lizard Anolis sagrei.

How individuals move through their environment dictates which other individuals they encounter, determining their social and reproductive interactions and the extent to which they experience sexual selection. Specifically, females rarely have the option of mating with all males in a population--they can only choose among the males they encounter. Further, quantifying phenotypic differences between the males that females encounter and those that sire females offspring lends insight into how social and reproductive interactions shape male phenotypes. We used an explicitly spatiotemporal Markov chain model to estimate the number of potential mates of Anolis sagrei lizards from their movement behavior, and used genetic paternity assignments to quantify sexual selection on males. Females frequently encountered and mated with multiple males, offering ample opportunity for female mate choice. Sexual selection favored males that were bigger and moved over larger areas, though the effect of body size cannot be disentangled from last-male precedence. Our approach corroborates some patterns of sexual selection previously hypothesized in anoles based on describing them as territorial, whereas other results, including female multiple mating itself, are at odds with territorial polygyny, offering insight into discrepancies in other taxa between behavioral and genetic descriptions of mating systems.

ecology↗

bioRxiv2017

The erratic and contingent progression of research on territoriality: a case study.

Our understanding of animal mating systems has changed dramatically with the advent of molecular methods to determine individuals reproductive success. But why are older behavioral descriptions and newer genetic descriptions of mating systems often seemingly inconsistent? We argue that a potentially important reason for such inconsistencies is a research trajectory rooted in early studies that were equivocal and overreaching, followed by studies that accepted earlier conclusions at face value and assumed, rather than tested, key ideas about animal mating systems. We illustrate our argument using Anolis lizards, whose social behavior has been studied for nearly a century. A dominant view emerging from this behavioral research was that anoles display strict territorial polygyny, where females mate with just the one male in whose territory they reside. However, all genetic evidence suggests that females frequently mate with multiple males. We trace this mismatch to early studies that concluded that anoles are territorial based on limited data. Subsequent research assumed territoriality implicitly or explicitly, resulting in studies that were unlikely to uncover or consider important any evidence of anoles departures from strict territorial polygyny. Thus, descriptions of anole behavior were largely led away from predicting a pattern of female multiple mating. We end by considering the broader implications of such erratic trajectories for the study of animal mating systems, and posit that precise definitions, renewed attention to natural history, and explicitly questioning assumptions made while collecting behavioral observations will allow us to move towards a fuller understanding of animal mating systems.

animal behavior and cognition↗