Hunting human disease genes: lessons from the past, challenges for the future

The concept that a specific alteration in an individual’s DNA can result in disease is central to our notion of molecular medicine. The molecular basis of more than 3,500 Mendelian disorders has now been identified. In contrast, the identification of genes for common disease has been much more challenging. We discuss historical and contemporary approaches to disease gene identification, focusing on novel opportunities such as the use of population extremes and the identification of rare variants. While our ability to sequence DNA has advanced dramatically, assigning function to a given sequence change remains a major challenge, highlighting the need for both bioinformatics and functional approaches to appropriately interpret these data. We review progress in mapping and identifying human disease genes and discuss future challenges and opportunities for the field

Ambiguity Aversion in Rhesus Macaques

People generally prefer risky options, which have fully specified outcome probabilities, to ambiguous options, which have unspecified probabilities. This preference, formalized in economics, is strong enough that people will reliably prefer a risky option to an ambiguous option with a greater expected value. Explanations for ambiguity aversion often invoke uniquely human faculties like language, self-justification, or a desire to avoid public embarrassment. Challenging these ideas, here we demonstrate that a preference for unambiguous options is shared with rhesus macaques. We trained four monkeys to choose between pairs of options that both offered explicitly cued probabilities of large and small juice outcomes. We then introduced occasional trials where one of the options was obscured and examined their resulting preferences; we ran humans in a parallel experiment on a nearly identical task. We found that monkeys reliably preferred risky options to ambiguous ones, even when this bias was costly, closely matching the behavior of humans in the analogous task. Notably, ambiguity aversion varied parametrically with the extent of ambiguity. As expected, ambiguity aversion gradually declined as monkeys learned the underlying probability distribution of rewards. These data indicate that ambiguity aversion reflects fundamental cognitive biases shared with other animals rather than uniquely human factors guiding decisions

Decision Salience Signals in Posterior Cingulate Cortex

Despite its phylogenetic antiquity and clinical importance, the posterior cingulate cortex (CGp) remains an enigmatic nexus of attention, memory, motivation, and decision making. Here we show that CGp neurons track decision salience – the degree to which an option differs from a standard – but not the subjective value of a decision. To do this, we recorded the spiking activity of CGp neurons in monkeys choosing between options varying in reward-related risk, delay to reward, and social outcomes, each of which varied in level of decision salience. Firing rates were higher when monkeys chose the risky option, consistent with their risk-seeking preferences, but were also higher when monkeys chose the delayed and social options, contradicting their preferences. Thus, across decision contexts, neuronal activity was uncorrelated with how much monkeys valued a given option, as inferred from choice. Instead, neuronal activity signaled the deviation of the chosen option from the standard, independently of how it differed. The observed decision salience signals suggest a role for CGp in the flexible allocation of neural resources to motivationally significant information, akin to the role of attention in selective processing of sensory inputs

Imprints of radial migration on the Milky Way’s metallicity distribution functions

Recent analysis of the SDSS-III/Apache Point Observatory Galactic Evolution Experiment (APOGEE) Data Release 12 stellar catalog has revealed that the Milky Way’s (MW) metallicity distribution function (MDF) changes shape as a function of radius, transitioning from being negatively skewed at small Galactocentric radii to positively skewed at large Galactocentric radii. Using a high-resolution, N-body+SPH simulation, we show that the changing skewness arises from radial migration—metal-rich stars form in the inner disk and subsequently migrate to the metal-poorer outer disk. These migrated stars represent a large fraction (>50%) of the stars in the outer disk; they populate the high-metallicity tail of the MDFs and are, in general, more metal-rich than the surrounding outer disk gas. The simulation also reproduces another surprising APOGEE result: the spatially invariant high-[α/Fe] MDFs. This arises in the simulation from the migration of a population formed within a narrow range of radii (3.2 ±1.2 kpc) and time (8.8 ± 0.6 Gyr ago), rather than from spatially extended star formation in a homogeneous medium at early times. These results point toward the crucial role radial migration has played in shaping our MW

Calciphylaxis following kidney transplantation: a case report

Introduction: Calciphylaxis occurring after kidney transplantation is rare and rarely reported. It results in chronic non-healing wounds and is associated with a poor prognosis and is often fatal. We present a case of proximal lower limb calciphylaxis that occurred early after kidney transplantation. The patient had no classic associated risk factors. He had previously had a total parathyroidectomy but had normal serum calcium-phosphate product and parathyroid hormone levels. The clinical outcome of this case was favorable and highlights some fundamental issues relating to management. Case prsentation: A 70-year-old British Caucasian man with end-stage renal failure secondary to IgA nephropathy presented six months post kidney transplantation with cutaneous calciphylaxis lesions involving the medial aspect of the thigh bilaterally. Conclusion: To the best of our knowledge, this is the first reported case of rapid onset cutaneous calciphylaxis occurring soon after kidney transplantation that was associated with a favorable outcome. Cutaneous calciphylaxis lesions should be promptly managed with meticulous wound care, antimicrobial therapy and the correction of calcium-phosphate product where indicated

Accurate Prediction of the Functional Significance of Single Nucleotide Polymorphisms and Mutations in the ABCA1 Gene

The human genome contains an estimated 100,000 to 300,000 DNA variants that alter an amino acid in an encoded protein. However, our ability to predict which of these variants are functionally significant is limited. We used a bioinformatics approach to define the functional significance of genetic variation in the ABCA1 gene, a cholesterol transporter crucial for the metabolism of high density lipoprotein cholesterol. To predict the functional consequence of each coding single nucleotide polymorphism and mutation in this gene, we calculated a substitution position-specific evolutionary conservation score for each variant, which considers site-specific variation among evolutionarily related proteins. To test the bioinformatics predictions experimentally, we evaluated the biochemical consequence of these sequence variants by examining the ability of cell lines stably transfected with the ABCA1 alleles to elicit cholesterol efflux. Our bioinformatics approach correctly predicted the functional impact of greater than 94% of the naturally occurring variants we assessed. The bioinformatics predictions were significantly correlated with the degree of functional impairment of ABCA1 mutations (r (2) = 0.62, p = 0.0008). These results have allowed us to define the impact of genetic variation on ABCA1 function and to suggest that the in silico evolutionary approach we used may be a useful tool in general for predicting the effects of DNA variation on gene function. In addition, our data suggest that considering patterns of positive selection, along with patterns of negative selection such as evolutionary conservation, may improve our ability to predict the functional effects of amino acid variation

Ruptured heterotopic pregnancy presenting as hemorrhagic shock

Background: Heterotopic pregnancy is a rare event consisting of simultaneous intrauterine and extrauterine pregnancies. If undiagnosed, it is probable the patient will present to an Emergency Department and require emergent care. Case Report: A 25 year-old woman arrived at the Emergency Department at 14 weeks gestation reporting sharp abdominal cramping and pelvic pain with a history of current tobacco use. Trans-abdominal ultrasound revealed a viable intrauterine pregnancy consistent with 14 weeks, closed cervix with free fluid noted in pelvis, and no evidence of ovarian torsion. Over the next three hours, the patient’s condition deteriorated and hemoglobin levels dropped. The surgeon on call was consulted and suspected ruptured hepatic adenoma versus hepatic hemangioma versus visceral aneurysm. A laparotomy was emergently performed with supraceliac control of aorta to permit resuscitation, and the right and left upper quadrants of the abdominal cavity were investigated without discovery of bleeding source. Further investigation revealed ruptured left tubal ectopic pregnancy and a partial salpingectomy was performed. Conclusions: This case serves as a clinical reminder that while heterotopic pregnancy is thought to be rare, when a patient presents with known intrauterine pregnancy and abdominal pain, heterotopic pregnancy should be included in the differential diagnosis. More common use of assisted reproductive technology may increase the incidence of heterotopic pregnancies, making familiarity with the signs, symptoms, and risk factors for this condition important

Semi-orthogonal subspaces for value mediate a tradeoff between binding and generalization

When choosing between options, we must associate their values with the action needed to select them. We hypothesize that the brain solves this binding problem through neural population subspaces. To test this hypothesis, we examined neuronal responses in five reward-sensitive regions in macaques performing a risky choice task with sequential offers. Surprisingly, in all areas, the neural population encoded the values of offers presented on the left and right in distinct subspaces. We show that the encoding we observe is sufficient to bind the values of the offers to their respective positions in space while preserving abstract value information, which may be important for rapid learning and generalization to novel contexts. Moreover, after both offers have been presented, all areas encode the value of the first and second offers in orthogonal subspaces. In this case as well, the orthogonalization provides binding. Our binding-by-subspace hypothesis makes two novel predictions borne out by the data. First, behavioral errors should correlate with putative spatial (but not temporal) misbinding in the neural representation. Second, the specific representational geometry that we observe across animals also indicates that behavioral errors should increase when offers have low or high values, compared to when they have medium values, even when controlling for value difference. Together, these results support the idea that the brain makes use of semi-orthogonal subspaces to bind features together.Comment: arXiv admin note: substantial text overlap with arXiv:2205.0676