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Goldberg, M. E.

Publications and source records attributed to Goldberg, M. E..

At least 19 recordsLinked to original sources
bioRxiv2026

A family portrait of the genomic factors shaping tandem repeat mutagenesis

Tandem repeats (TRs) are among the most mutable loci in the human genome, but the genomic determinants of TR mutagenesis remain mysterious. We used PacBio HiFi long-read sequencing to profile nearly eight million TR loci in 28 members of a large, four-generation CEPH/Utah family designated K1463. We identified 1,270 de novo TR expansions and contractions across 20 children in the pedigree. De novo mutations (DNMs) were more likely to occur at loci that were longer, composed of uninterrupted motif sequences, and heterozygous in the parental germline. Children born to older fathers also exhibited more de novo mutations at short tandem repeats (STRs). A total of 43 TR loci were hyper-mutable in K1463, expanding or contracting up to twelve times across the pedigree. Among hyper-mutable loci that comprised multiple motifs (i.e., "complex" loci), specific motifs expanded and contracted more often than others; for example, all ten DNMs at a complex, hyper-mutable locus near the non-coding RNA LINC03021 involved the same 19bp motif. The mutability of particular motifs may be attributable to allele length, as 95% of DNMs at complex loci were expansions and contractions of the most abundant motif on a parental haplotype. However, future work will be required to disentangle the effects of nucleotide content and allele length on motif-specific mutability, especially at hyper-mutable TRs. Overall, this study combines long-read sequencing technologies with new software tools to comprehensively investigate the factors that influence TR mutagenesis.

genomics↗
bioRxiv2026

The performance of genetic-constraint metrics varies significantly across the human noncoding genome

A longstanding goal in human genetics is to prioritize noncoding loci that, when disrupted, lead to developmental disorders and other Mendelian traits. In pursuit of this goal, multiple metrics have been developed to distinguish neutrally evolving sequences from those subjected to purifying selection. These metrics are commonly evaluated genome-wide, e.g., by computing a precision-recall curve on windows tiling the entire noncoding genome. Here, we identify parts of the noncoding genome where these metrics significantly underperform relative to their genome-wide performance due to "bias" in the underlying models of neutral genetic variation and/or a low "signal-to-noise ratio" in the genetic data. The most extreme effects are found for Gnocchi (Chen et al. 2024), the performance of which declines as GC content increases. We suggest annotating constraint scores of noncoding genomic intervals with robust measures of the bias of the corresponding model, allowing users to gauge confidence in those scores.

genomics↗
bioRxiv2025

The selective dynamics of interruptions at short tandem repeats

Short tandem repeats (STRs) are hotspots of genomic instability that mutate at rates orders of magnitude greater than non-repetitive loci due to frequent replication slippage. Expansions at some STR loci cause Mendelian diseases, while variation at other noncoding loci may affect complex traits, possibly by altering transcription factor occupancy of nearby binding sites. Accordingly, some STRs are inferred to be under purifying selection, regardless of their instability. One or more "interruptions", or bases that disrupt the locuss canonical repeat, significantly decrease an STRs mutability. For example, the onset of Huntingtons Disease, a neurodegenerative disorder associated with somatic expansions of a trinucleotide coding STR, is delayed in individuals whose inherited alleles contain interruptions. Thus, interruptions that decrease mutation rate at some coding loci may broadly protect against deleterious phenotypes associated with locus instability. However, interruptions may themselves be deleterious at constrained loci, particularly at noncoding loci in gene regulatory elements, possibly disrupting the formation of secondary structures key to their function. We therefore hypothesized that the frequency of interruptions could depend on a locuss functional importance-at constrained loci, the fitness effects of expansions but also interruptions could be more deleterious than at neutral loci. To test this hypothesis, we examined the distribution of interruptions at [~]650,000 autosomal STRs. In the [~]2,500 3- or 6bp-motif coding STRs, we find that synonymous interruption density increases with purifying selection on the gene, while the opposite is true for missense-causing interruptions. In contrast, noncoding STRs in gene regulatory elements harbor fewer interruptions than those unassociated with function and putatively evolving neutrally. Our findings indicate that the abundance of interruptions may be partially explained at coding STRs by the benefit of lower instability. In contrast, maintaining a minimum core stretch of uninterrupted repeat may be key to the function of noncoding STRs that fall within regulatory elements, outweighing the benefits of stability.

evolutionary biology↗
bioRxiv2025

The Chimeric Peptide (GEP44) Reduces Body Weight, Energy Intake, and Energy Expenditure in Diet-Induced Obese Rats

We recently reported that a chimeric peptide (GEP44) targeting the glucagon-like peptide-1 receptor (GLP-1R) and neuropeptide Y1- and Y2-receptors decreased body weight (BW), energy intake and core temperature in diet-induced obese (DIO) male and female mice. In the current study, we tested the hypothesis that the strong reduction of body weight in response to GEP44 is partially related to the stimulation of energy expenditure (EE). To test this, rats were maintained on a HFD for at least 4 months to elicit DIO prior to undergoing a sequential 2-day vehicle period, 2-day GEP44 (50 nmol/kg) period and a minimum 2-day washout period and detailed measures of energy homeostasis. GEP44 (50 nmol/kg) reduced EE (indirect calorimetry), respiratory exchange ratio (RER), core temperature, activity, energy intake and BW in male and female rats. As in our previous study in mice, GEP44 reduced BW in male and female HFD-fed rats by 3.8 {+/-} 0.2% and 2.3 {+/-} 0.4%, respectively. These effects appear to be mediated by increased lipid oxidation and reductions of energy intake as GEP44 reduced RER and cumulative energy intake in male and female HFD-fed rats. The strong reduction of body weight in response to GEP44 is related to a robust reduction of energy intake, but not to stimulation of EE. The paradoxical finding that GEP44 reduced EE might be secondary to a reduction of diet-induced thermogenesis or might indicate an important mechanism to limit the overall efficacy of GEP44 to prevent further weight loss.

physiology↗
bioRxiv2024

A circuit model for transsaccadic space updating and mislocalization

We perceive a stable, continuous world despite drastic changes of retinal images across saccades. However, while persistent objects in daily life appear stable across saccades, stimuli flashed around saccades can be grossly mislocalized. We address this puzzle with our recently proposed circuit model for perisaccadic receptive-field (RF) remapping in LIP and FEF. The model uses center/surround connections to store a relevant stimulus retinal location in memory as a population activity. This activity profile is updated across each saccade by directional connections gated by the corollary discharge (CD) of the saccade command. The updating is a continuous backward (against the saccade) shift of the population activity (equivalent to continuous forward remapping of the RFs), whose cumulative effect across the saccade is a subtraction of the saccade vector. The model explains forward and backward translational mislocalization for stimuli flashed around the saccade onset and offset, respectively, as insufficient and unnecessary cumulative updating after the saccade, caused by the sluggish CD time course and visual response latency. We confirm the model prediction that for perisaccadic RFs measured with flashes before the saccades, the final forward remapping magnitudes after the saccades are smaller for later flashes. We discuss the possibility that compressive mislocalization results from a brief reduction of attentional remapping and repulsion. Although many models of RF remapping, transsaccadic updating, and perisaccadic mislocalization have been proposed, our work unifies them into a single circuit mechanism and suggests that the brain uses "unaware" decoders which do not distinguish between different origins of neurons activities.

neuroscience↗
bioRxiv2024

Purkinje cells in Crus I and II encode the visual stimulus and the impending choice as monkeys learn a reinforcement based visuomotor association task

Visuomotor association involves linking an arbitrary visual cue to a well-learned movement. Transient inactivation of Crus I/II impairs primates ability to learn new associations and delays motor responses without affecting the kinematics of the movement. The simple spikes of Purkinje cells in the Crus regions signal cognitive errors as monkeys learn to associate specific fractal stimuli with movements of the left or right hand. Here we show that as learning progresses, the simple spike activity of individual neurons becomes more selective for stimulus-response associations, with selectivity developing closer to the appearance of visual stimuli. Initially, most neurons respond to both associations, irrespective of the identity of the stimulus and the associated movement, but as learning advances, more neurons distinguish between specific stimulus-hand associations. Using a linear decoder, it was found that in early learning stages, the visual stimulus can be decoded only when the choice can also be decoded. As learning improves, the visual stimulus is decoded earlier than the choice. A simple model can replicate the observed simple spike signals and the monkeys behavior in both the early and late learning stages.

neuroscience↗
bioRxiv2024

A familial, telomere-to-telomere reference for human de novo mutation and recombination from a four-generation pedigree

Using five complementary short- and long-read sequencing technologies, we phased and assembled >95% of each diploid human genome in a four-generation, 28-member family (CEPH 1463) allowing us to systematically assess de novo mutations (DNMs) and recombination. From this family, we estimate an average of 192 DNMs per generation, including 75.5 de novo single-nucleotide variants (SNVs), 7.4 non-tandem repeat indels, 79.6 de novo indels or structural variants (SVs) originating from tandem repeats, 7.7 centromeric de novo SVs and SNVs, and 12.4 de novo Y chromosome events per generation. STRs and VNTRs are the most mutable with 32 loci exhibiting recurrent mutation through the generations. We accurately assemble 288 centromeres and six Y chromosomes across the generations, documenting de novo SVs, and demonstrate that the DNM rate varies by an order of magnitude depending on repeat content, length, and sequence identity. We show a strong paternal bias (75-81%) for all forms of germline DNM, yet we estimate that 17% of de novo SNVs are postzygotic in origin with no paternal bias. We place all this variation in the context of a high-resolution recombination map ([~]3.5 kbp breakpoint resolution). We observe a strong maternal recombination bias (1.36 maternal:paternal ratio) with a consistent reduction in the number of crossovers with increasing paternal (r=0.85) and maternal (r=0.65) age. However, we observe no correlation between meiotic crossover locations and de novo SVs, arguing against non-allelic homologous recombination as a predominant mechanism. The use of multiple orthogonal technologies, near-telomere-to-telomere phased genome assemblies, and a multi-generation family to assess transmission has created the most comprehensive, publicly available "truth set" of all classes of genomic variants. The resource can be used to test and benchmark new algorithms and technologies to understand the most fundamental processes underlying human genetic variation.

genomics↗
bioRxiv2023

Effects of parental age and polymer composition on short tandem repeat de novo mutation rates

Short tandem repeats (STRs) are hotspots of genomic variability in the human germline because of their high mutation rates, which have long been attributed largely to polymerase slippage during DNA replication. This model suggests that STR mutation rates should scale linearly with a fathers age, as progenitor cells continually divide after puberty. In contrast, it suggests that STR mutation rates should not scale with a mothers age at her childs conception, since oocytes spend a mothers reproductive years arrested in meiosis II and undergo a fixed number of cell divisions that are independent of the age at ovulation. Yet, mirroring recent findings, we find that STR mutation rates covary with paternal and maternal age, implying that some STR mutations are caused by DNA damage in quiescent cells rather than the classical mechanism of polymerase slippage in replicating progenitor cells. These results also echo the recent finding that DNA damage in quiescent oocytes is a significant source of de novo SNVs and corroborate evidence of STR expansion in postmitotic cells. However, we find that the maternal age effect is not confined to previously discovered hotspots of oocyte mutagenesis, nor are post-zygotic mutations likely to contribute significantly. STR nucleotide composition demonstrates divergent effects on DNM rates between sexes. Unlike the paternal lineage, maternally derived DNMs at A/T STRs display a significantly greater association with maternal age than DNMs at GC-containing STRs. These observations may suggest the mechanism and developmental timing of certain STR mutations and are especially surprising considering the prior belief in replication slippage as the dominant mechanism of STR mutagenesis. Author SummaryWe have long known that tandem repeats are hypermutable and attributed that hypermutability to slippage during DNA replication. Contradicting this long-held theory, we show that tandem repeats accumulate mutations in maternal germ cells during periods when these cells do not replicate. This bolsters a new consensus that DNA replication is not the only driver of mutagenesis, even at loci where replicative slippage is possible. Patterns shared by certain loci enriched for mutations from older mothers may hint at mechanisms.

evolutionary biology↗
bioRxiv2023

Mice require proprioception to establish long-term visuospatial memory.

Because the retina moves constantly, the retinotopic representation of the visual world is spatially inaccurate and the brain must transform this spatially inaccurate retinal signal to a spatially accurate signal usable for perception and action. One of the salient discoveries of modern neuroscience is the role of the hippocampus in establishing gaze-independent, long-term visuospatial memories. The rat hippocampus has neurons which report the animals position in space regardless of its angle of gaze. Rats with hippocampal lesions are unable to find the location of an escape platform hidden in a pool of opaque fluid, the Morris Water Maze (MWM) based on the visual aspects of their surrounding environment. Here we show that the representation of proprioception in the dysgranular zone of primary somatosensory cortex is equivalently necessary for mice to learn the location of the hidden platform, presumably because without it they cannot create a long-term gaze-independent visuospatial representation of their environment from the retinal signal. They have no trouble finding the platform when it is marked by a flag, and they have no motor or vestibular deficits.

neuroscience↗
bioRxiv2023

Perisaccadic and Attentional Remapping of Receptive Fields in Lateral Intraparietal Area and Frontal Eye Fields

The nature and function of perisaccadic receptive-field (RF) remapping have been controversial. We used a delayed saccade task to reduce previous confounds and examined the remapping time course in areas LIP and FEF. In the delay period, the RF shift direction turned from the initial fixation to the saccade target. In the perisaccadic period, RFs first shifted toward the target (convergent remapping) but around the time of saccade onset/offset, the shifts became predominantly toward the post-saccadic RF locations (forward remapping). Thus, unlike forward remapping that depends on the corollary discharge (CD) of the saccade command, convergent remapping appeared to follow attention from the initial fixation to the target. We modelled the data with attention-modulated and CD-gated connections, and showed that both sets of connections emerged automatically in neural networks trained to update stimulus retinal locations across saccades. Our work thus unifies previous findings into a mechanism for transsaccadic visual stability.

neuroscience↗
bioRxiv2022

Increased mutation rate and interlocus gene conversion within human segmental duplications.

Single-nucleotide variants (SNVs) within segmental duplications (SDs) have not been systematically assessed because of the difficulty in mapping short-read sequence data to virtually identical repetitive sequences. Using 102 phased human haplotypes, we constructed 1:1 unambiguous alignments spanning high-identity SDs and compared the pattern of SNVs between unique and SD regions. We find that human SNVs are elevated 60% in SDs compared to unique regions. We estimate that at least 23% of this increase is due to interlocus gene conversion (IGC) with >7 Mbp of SD sequence converted on average per human haplotype. We develop a genome-wide map of IGC donors and acceptors, including 498 acceptor and 454 donor hotspots affecting the exons of ~800 protein-coding genes. The latter includes 171 genes that have "relocated" on average 1.61 Mbp in a subset of human haplotypes. Using a coalescent framework, we show that SD regions are evolutionarily older when compared to unique sequences with most of this signal originating from putative IGC loci. SNVs within SDs, however, also exhibit a distinct mutational spectrum where there is a 27.1% increase in transversions that convert cytosine to guanine or the reverse across all triplet contexts. In addition, we observe a 7.6% reduction in the frequency of CpG associated mutations when compared to unique DNA. We hypothesize that these distinct mutational properties help to maintain an overall higher GC content of SD DNA when compared to unique DNA, and we show that these GC-favoring mutational events are likely driven by GC-biased conversion between paralogous sequences.

genomics↗
bioRxiv2021

Mixed selectivity in the cerebellar Purkinje-cell response during visuomotor association learning

Although the cerebellum has been traditionally considered to be exclusively involved in motor control, recent anatomical and clinical studies show that it also has a role in reward-processing. However, the way in which the movement related and the reward related neural activity interact at the level of the cerebellar cortex and contribute towards learning is still unclear. Here, we studied the simple spike activity of Purkinje cells in the mid-lateral cerebellum when monkeys learned to associate a right or left-hand movement with one of two visual symbolic cues. These cells had distinctly different discharge patterns between an overtrained symbol-hand association and a novel symbol-hand association, responding in association with the movement of both hands, although the kinematics of the movement did not change between the two conditions. The activity change was not related to the pattern of the visual symbols, the movement kinematics, the monkeys reaction times or the novelty of the visual symbols. The simple spike activity changed with throughout the learning process, but the concurrent complex spikes did not instruct that change. Although these neurons also have reward-related activity, the reward-related and movement-related signals were independent. We suggest that this mixed-selectivity may facilitate the flexible learning of difficult reinforcement learning problems.

neuroscience↗
bioRxiv2020

The mid-lateral cerebellum is necessary for reinforcement learning

The cerebellum has long been considered crucial for supervised motor learning and its optimization1-3. However, new evidence has also implicated the cerebellum in reward based learning4-8, executive function9-12, and frontal-like clinical deficits13. We recently showed that the simple spikes of Purkinje cells (P-cells) in the mid-lateral cerebellar hemisphere (Crus I and II) encode a reinforcement error signal when monkeys learn to associate arbitrary symbols with hand movements4. However, it is unclear if the cerebellum is necessary for any process beyond motor learning. To investigate if the mid-lateral cerebellum is actually necessary for learning visuomotor associations, we reversibly inactivated the mid-lateral cerebellum of two primates with muscimol while they learned to associate arbitrary symbols with hand movements. Here we show that cerebellar inactivation impaired the monkeys ability to learn new associations, although it had no effect on the monkeys performance on a task with overtrained symbols. A computational model corroborates our results. Cerebellar inactivation increased the reaction time, but there were no deficits in any motor kinematics such as the hand movement, licking or eye movement. There was no loss of function when we inactivated a more anterior region of the cerebellum that is implicated in motor control. We suggest that the mid-lateral cerebellum, which provides a reinforcement learning error signal4, is necessary for visuomotor association learning. Our results have implications for the involvement of cerebellum in cognitive control, and add critical constraints to brain models of non-motor learning14,15.

neuroscience↗
bioRxiv2019

Neural correlates of goal-directed and non-goal-directed movements

What are the neural correlates that distinguish goal-directed (G) from non-goal-directed movements (nG)? We investigated this question in the monkey frontal eye field, which is implicated in voluntary control of saccades. We found that only for G-saccades, the variability in spike rate across trials decreased, the regularity of spike timings within trials increased, the neural activity increased earlier from baseline and had a concurrent reduction of LFP beta band power.

neuroscience↗
bioRxiv2019

Complex spikes encode reward expectation signals during visuomotor association learning

Climbing fiber input to Purkinje cells has been thought to instruct learning related changes in simple spikes and cause behavioral changes through an error-based learning mechanism. Although, this framework explains simple motor learning, it cannot be extended to learning higher-order skills. Recently the cerebellum has been implicated in a variety of cognitive tasks and reward-based learning. Here we show that when a monkey learns a new visuomotor association, complex spikes predict the time of the beginning of the trial in a learning independent manner as well as encode a learning contingent reward expectation signal after the stimulus onset and reward delivery. These complex spike signals are unrelated to and were unlikely to instruct the reward based signal found in the simple spikes. Our results provide a more general role of complex spikes in learning and higher-order processing while gathering evidence for their participation in reward based learning.

neuroscience↗
bioRxiv2019

Great ape mutation spectra vary across the phylogeny and the genome due to distinct mutational processes that evolve at different rates

Great ape clades exhibit variation in the relative mutation rates of different three-base-pair genomic motifs, with closely related species having more similar mutation spectra than distantly related species. This pattern cannot be explained by classical demographic or selective forces, but imply that DNA replication fidelity has been perturbed in different ways on each branch of the great ape phylogeny. Here, we use whole-genome variation from 88 great apes to investigate whether these species mutation spectra are broadly differentiated across the entire genome, or whether mutation spectrum differences are driven by DNA compartments that have particular functional features or chromatin states. We perform principal component analysis and mutational signature deconvolution on mutation spectra ascertained from compartments defined by features including replication timing and ancient repeat content, finding evidence for consistent species-specific mutational signatures that do not depend on which functional compartments the spectra are ascertained from. At the same time, we find that many compartments have their own characteristic mutational signatures that appear stable across the great ape phylogeny. For example, in a mutation spectrum PCA compartmentalized by replication timing, the second PC explaining 21.2% of variation separates all species late-replicating regions from their early-replicating regions. Our results suggest that great ape mutation spectrum evolution is not driven by epigenetic changes that modify mutation rates in specific genomic regions, but instead by trans-acting mutational modifiers that affect mutagenesis across the whole genome fairly uniformly. SIGNIFICANCE STATEMENTAll heritable variation begins with damage or copying mistakes affecting the DNA of sperm, eggs, or embryos. Different DNA motifs can have different mutation rates, and these rates can evolve over time: the spectrum of mutability of three-base-pair motifs has evolved rapidly during great ape diversification. Here, we show that even as ape mutation spectra diverged from each other, ape genomes preserved a landscape of spatial mutation spectrum variation. We can thus deconvolute the mutational process into a mixture of fast-evolving signatures with uniform spatial distributions and conserved signatures that target specific regions. Our findings may ultimately help determine the factors, either genetic or environmental, that contribute to temporal and spatial variation in germline mutagenesis.

genomics↗
bioRxiv2019

Mid-lateral Cerebellar Purkinje Cells Provide a Cognitive Error Signal When Monkeys Learn a New Visuomotor Association

How do we learn to establish associations between arbitrary visual cues (like a red light) and movements (like braking the car)? We investigated the neural correlates of visuomotor association learning in the monkey mid-lateral cerebellum. Here we show that, during learning but not when the associations were overlearned, individual Purkinje cells reported the outcome of the monkeys most recent decision, an error signal, which was independent of changes in hand movement or reaction time. At the population level, Purkinje cells collectively maintained a memory of the most recent decision throughout the entire trial period, updating it after every decision. This error signal decreased as the performance improved. Our results suggest a role of mid-lateral cerebellum in visuomotor associative learning and provide evidence that cerebellum could be a generalized learning system, essential in non-motor learning as well as motor learning.

neuroscience↗