Functional, Morphological, and Evolutionary Characterization of Hearing in Subterranean, Eusocial African Mole-Rats

Naked mole-rats are highly vocal, eusocial, subterranean rodents with, counterintuitively, poor hearing. The causes underlying their altered hearing are unknown. Moreover, whether altered hearing is degenerate or adaptive to their unique lifestyles is controversial. We used various methods to identify the factors contributing to altered hearing in naked and the related Damaraland mole-rats and to examine whether these alterations result from relaxed or adaptive selection. Remarkably, we found that cochlear amplification was absent from both species despite normal prestin function in outer hair cells isolated from naked mole-rats. Instead, loss of cochlear amplification appears to result from abnormal hair bundle morphologies observed in both species. By exploiting a well-curated deafness phenotype-genotype database, we identified amino acid substitutions consistent with abnormal hair bundle morphology and reduced hearing sensitivity. Amino acid substitutions were found in unique groups of six hair bundle link proteins. Molecular evolutionary analyses revealed shifts in selection pressure at both the gene and the codon level for five of these six hair bundle link proteins. Substitutions in three of these proteins are associated exclusively with altered hearing. Altogether, our findings identify the likely mechanism of altered hearing in African mole-rats, making them the only identified mammals naturally lacking cochlear amplification. Moreover, our findings suggest that altered hearing in African mole-rats is adaptive, perhaps tailoring hearing to eusocial and subterranean lifestyles. Finally, our work reveals multiple, unique evolutionary trajectories in African mole-rat hearing and establishes species members as naturally occurring disease models to investigate human hearing loss

Defining the causes of sporadic Parkinson's disease in the global Parkinson's genetics program (GP2)

The Global Parkinson's Genetics Program (GP2) will genotype over 150,000 participants from around the world, and integrate genetic and clinical data for use in large-scale analyses to dramatically expand our understanding of the genetic architecture of PD. This report details the workflow for cohort integration into the complex arm of GP2, and together with our outline of the monogenic hub in a companion paper, provides a generalizable blueprint for establishing large scale collaborative research consortia

Defining the causes of sporadic Parkinson’s disease in the global Parkinson’s genetics program (GP2)

The Global Parkinson’s Genetics Program (GP2) will genotype over 150,000 participants from around the world, and integrate genetic and clinical data for use in large-scale analyses to dramatically expand our understanding of the genetic architecture of PD. This report details the workflow for cohort integration into the complex arm of GP2, and together with our outline of the monogenic hub in a companion paper, provides a generalizable blueprint for establishing large scale collaborative research consortia

Defining the causes of sporadic Parkinson's disease in the global Parkinson's genetics program (GP2)

The Global Parkinson’s Genetics Program (GP2) will genotype over 150,000 participants from around the world, and integrate genetic and clinical data for use in large-scale analyses to dramatically expand our understanding of the genetic architecture of PD. This report details the workflow for cohort integration into the complex arm of GP2, and together with our outline of the monogenic hub in a companion paper, provides a generalizable blueprint for establishing large scale collaborative research consortia

Multi-ancestry genome-wide association meta-analysis of Parkinson?s disease

Although over 90 independent risk variants have been identified for Parkinson’s disease using genome-wide association studies, most studies have been performed in just one population at a time. Here we performed a large-scale multi-ancestry meta-analysis of Parkinson’s disease with 49,049 cases, 18,785 proxy cases and 2,458,063 controls including individuals of European, East Asian, Latin American and African ancestry. In a meta-analysis, we identified 78 independent genome-wide significant loci, including 12 potentially novel loci (MTF2, PIK3CA, ADD1, SYBU, IRS2, USP8, PIGL, FASN, MYLK2, USP25, EP300 and PPP6R2) and fine-mapped 6 putative causal variants at 6 known PD loci. By combining our results with publicly available eQTL data, we identified 25 putative risk genes in these novel loci whose expression is associated with PD risk. This work lays the groundwork for future efforts aimed at identifying PD loci in non-European populations

Social isolation produces no effect on ultrasonic vocalization production in adult female CBA/CaJ mice.

Mice produce ultrasonic vocalizations (USVs) in a wide variety of social contexts, including courtship, investigation, and territorial defense. Despite the belief that mouse USVs are innate, social experience may be necessary for mice to learn the appropriate situation to emit USVs. Mouse USVs have been divided into categories based on their spectrotemporal parameters, but it is currently unclear if social experience changes these parameters (e.g., frequency and duration) or the proportion of calls from each category produced. Social isolation has been found to influence USV production in male mice. To investigate the influence of social isolation on vocal behavior in female mice, recordings were made of USVs emitted to unfamiliar male and female mice by subjects with one of three types of social experience. Twenty-four adult female CBA/CaJ mice either lived alone, lived with other females only, or lived with other females and had limited access to a male. Mice were recorded while in isolation, ensuring all recorded USVs were from the female of interest. Vocalizations were separated into nine categories and peak frequency, duration, and bandwidth were measured for every call. Socially isolated mice did not produce significantly more USVs or USV types than socially experienced mice. Social isolation did not have a significant effect on the features of USVs, suggesting production of USVs may not be learned in female mice

CBA/CaJ mouse ultrasonic vocalizations depend on prior social experience.

Mouse ultrasonic vocalizations (USVs) have variable spectrotemporal features, which researchers use to parse them into different categories. USVs may be important for communication, but it is unclear whether the categories that researchers have developed are relevant to the mice. Instead, other properties such as the number, rate, peak frequency, or bandwidth of the vocalizations may be important cues that the mice are using to interpret the nature of the social interaction. To investigate this, a comprehensive catalog of the USVs that mice are producing across different social contexts must be created. Forty male and female adult CBA/CaJ mice were recorded in isolation for five minutes following either a one-hour period of isolation or an exposure to a same- or opposite-sex mouse. Vocalizations were separated into nine categories based on the frequency composition of each USV. Additionally, USVs were quantified based on the bandwidth, duration, peak frequency, total number, and proportion of vocalizations produced. Results indicate that mice differentially produce their vocalizations across social encounters. There were significant differences in the number of USVs that mice produce across exposure conditions, the proportional probability of producing the different categories of USVs across sex and conditions, and the features of the USVs across conditions. In sum, there are sex-specific differences in production of USVs by laboratory mice, and prior social experiences matter for vocalization production. Furthermore, this study provides critical evidence that female mice probably produce vocalizations in opposite-sex interactions, which is important because this is an often overlooked variable in mouse communication research

The mean proportion of USV types produced by males and females across exposure conditions.

<p>The left column is females and the right column is males. The top row is the isolated condition, the middle row is the same sex exposure condition, and the bottom row is the opposite sex exposure condition. The different colors/shadings represent the mean proportion of each of the nine different categories of ultrasonic vocalizations.</p

Number of vocalizations across exposure conditions.

<p><b>(a)</b> Box plot showing the range of vocalizations produced across exposure conditions, the median (line in the box), and 95% confidence intervals. The black dots represent data points that lie outside the 10^th and 90^th percentiles. The isolate condition is shown in black, the same-sex condition is shown in gray, and the opposite sex condition is shown in white. The * represent significantly different conditions. <b>(b)</b> Box plot showing the range of vocalizations produced across exposure conditions, the median (line in the box), and 95% confidence intervals. The black dots represent data points that lie outside the 10^th and 90^th percentiles. The left half of the figure is females and the right half of the figure is males. The isolated condition is shown in black, the same-sex exposure condition is shown in gray, and the opposite-sex exposure condition is shown in white.</p

Recording chamber.

<p>The recording chamber was a standard mouse cage lined with a paper towel to reduce noise. The recording cage was placed into a homemade double walled sound attenuated booth lined with anechoic foam. An ultrasonic condenser microphone was placed above the recording cage pointing downwards. Mice were recorded in this chamber in acoustic isolation for five minutes.</p