Biology subjects

Rubio Garcia, A.

Publications and source records attributed to Rubio Garcia, A..

6 recordsLinked to original sources

bioRxiv2021

Vocal tract allometry in a mammalian vocal learner

Acoustic allometry occurs when features of animal vocalisations can be predicted from body size measurements. Despite this being considered the norm, allometry sometimes breaks, resulting in species sounding smaller or larger than expected for their size. A recent hypothesis suggests that allometry-breaking mammals cluster into two groups: those with anatomical adaptations to their vocal tracts and those capable of learning new sounds (vocal learners). Here we test which mechanism is used to escape from acoustic allometry by probing vocal tract allometry in a proven mammalian vocal learner, the harbour seal (Phoca vitulina). We test whether vocal tract structures and body size scale allometrically in 68 young individuals. We find that both body length and body mass accurately predict vocal tract length and one tracheal dimension. Independently, body length predicts vocal fold length while body mass predicts a second tracheal dimension. All vocal tract measures are larger in weaners than in pups and some structures are sexually dimorphic within age classes. We conclude that harbour seals do comply with anatomical allometric constraints. However, allometry between body size and vocal fold length seems to emerge after puppyhood, suggesting that ontogeny may modulate the anatomy-learning distinction previously hypothesised as clear-cut. We suggest that seals, like other species producing signals that deviate from those expected from their vocal tract dimensions, may break allometry without morphological adaptations. In seals, and potentially other vocal learning mammals, advanced neural control over vocal organs may be the main mechanism for breaking acoustic allometry.

animal behavior and cognition↗

bioRxiv2021

Thymocyte regulatory variant alters transcription factor binding and protects from type 1 diabetes in infants

We recently mapped a genetic susceptibility locus on chromosome 6q22.33 for type 1 diabetes diagnosed below age of 7 years near the gene Protein tyrosine phosphatase receptor type K (PTPRK) and the thymocyte selection associated gene (THEMIS). As the thymus plays a central role in shaping the T cell repertoire, we aimed to identify the most likely causal genetic factors behind the association using thymocyte genomic data. In four thymocyte populations we identified 253 DNA sequence motifs underlying histone modifications. The G insertion allele of rs138300818, associated with protection from diabetes, created thymocyte motifs for multiple histone modifications and thymocyte types. The insertion also disrupted a predicted RFX5/7 transcription factor binding site. RFX7 is abundantly expressed in thymus. Chromatin state and RNA sequencing data suggested strong transcription overlapping rs138300818 in fetal thymus, while eQTL and chromatin conformation data indicated that the rs138300818 insertion is associated with lower THEMIS expression. Taken together, our results support a role for thymic THEMIS gene expression and the rs138300818 variant in promoting the development and diagnosis of type 1 diabetes at an earlier age.

genetics↗

bioRxiv2021

HLA class II mediates type 1 diabetes risk by anti-insulin repertoire selection

Type 1 diabetes (T1D) is a common autoimmune disorder characterized by the destruction of insulin-secreting pancreatic {beta} cells [1], in which polymorphism of the human leukocyte antigen (HLA) class II region is the major genetic risk factor [2, 3, 4]. However, how variation in class II molecules alters T1D risk remains a longstanding question. Here we show how T1D risk due to HLA class II haplotype combinations [5] correlates with the frequency of negatively charged sequences in the CDR3{beta} region of CD4+ T cell receptor (TCR) repertoires purified from peripheral blood. These sequences are known to be common in receptors that bind insulin B:9-23 [6], the primary autoantigen in T1D. We also show the same effect in circulating activated CD4+ T cells from newly-diagnosed T1D cases, and in islet-infiltrating T cells from patients with active T1D. Furthermore, we demonstrate that the proportion of insulin-reactive CD4+ T cells present in islets is predicted by the frequency of these negatively charged CDR3{beta} amino acid sequences. Our results suggest diagnostic uses of T cell repertoire profiling in early detection of insulin autoimmunity, and inform ongoing efforts to improve tolerance induction to insulin and prevention of T1D [7].

genomics↗

bioRxiv2019

Peripheral tolerance to insulin is encoded by mimicry in the microbiome

How organisms achieve sustained peripheral tolerance throughout their lifetime, a correct immune discrimination between self and non-self, remains poorly understood. Host-microbiome interactions carry fundamental information that facilitates this process. We hypothesize that commensal microbes are under evolutionary pressure to develop epitopes that, when presented along with other antigens from their own bacterial community, lead to an overall tolerogenic self classification by the host immune system. Hosts, which have co-evolved with commensals, may rely on mimotopes, bacterial epitopes that are indistinguishable from key self epitopes, as a homeostatic feedback mechanism to establish and maintain tolerance. Using a probabilistic sequence model of peptide mimicry, we show that the gut microbiome contains a set of genes that are likely to trigger identical immune responses to insulin B 9-25, a widely distributed self epitope across tissues and the primary autoantigen in type 1 diabetes. Similarities in the antigen receptor sequences determined from CD4 T cells reacting to insulin epitopes and mimotopes provide experimental evidence for mimicry. All predicted high posterior probability mimotopes belong to the transketolase superfamily, an enzyme that allows efficient harvest of commensal-derived sugar polymers and dietary fibre, an advantage during host colonisation. Microbial transketolase upregulation during infant weaning coincides in time with the peak in autoantibody development against insulin. Abundance changes in bacterial genera that carry these mimotopes have also been observed to precede disease diagnosis. Our findings suggest gut dysbiosis followed by immune response to insulin mimotopes as a primary cause of type 1 diabetes, and may contribute towards unraveling similar causal patterns in a wide variety of disorders.

immunology↗

bioRxiv2018

The plasma biomarker soluble SIGLEC-1 is associated with the type I interferon transcriptional signature, ethnic background and renal disease in systemic lupus erythematosus

The molecular heterogeneity of autoimmune and inflammatory diseases has been one of the main obstacles to the development of safe and specific therapeutic options. Here we have evaluated the diagnostic and clinical value of a robust, inexpensive, immunoassay detecting the circulating soluble form of the monocyte-specific surface receptor sialic acid binding Ig-like lectin 1 (sSIGLEC-1).\n\nWe developed an immunoassay to measure sSIGLEC-1 in small volumes of plasma/serum from systemic lupus erythematosus (SLE) patients and healthy donors. Plasma concentrations of sSIGLEC-1 strongly correlated with expression of SIGLEC-1 on the surface of blood monocytes and with type I interferon (IFN)-regulated gene (IRG) expression in SLE patients. In addition, we identified marked ancestry-related differences in sSIGLEC-1 concentrations in SLE patients, with patients of non-European ancestry showing higher levels compared to patients of European ancestry. Higher sSIGLEC-1 concentrations were associated with lower serum complement component 3 and increased frequency of renal complications in European patients, but not with the SLEDAI clinical score.\n\nOur sSIGLEC-1 immunoassay provides a specific and easily-assayed marker for monocyte-macrophage activation, and interferonopathy in SLE and other diseases. Further studies can extend its clinical associations and its potential use to stratify patients and as a secondary endpoint in trials.

immunology↗

bioRxiv2017

Chromosome contacts in activated T cells identify autoimmune disease-candidate genes

BackgroundAutoimmune disease-associated variants are preferentially found in regulatory regions in immune cells, particularly CD4+ T cells. Linking such regulatory regions to gene promoters in disease-relevant cell contexts facilitates identification of candidate disease genes.\n\nResultsWithin four hours, activation of CD4+ T cells invokes changes in histone modifications and enhancer RNA transcription that correspond to altered expression of the interacting genes identified by promoter capture Hi-C. By integrating promoter capture Hi-C data with genetic associations for five autoimmune diseases we prioritised 245 candidate genes with a median distance from peak signal to prioritised gene of 153 kb. Just under half (108/245) prioritised genes related to activation-sensitive interactions. This included IL2RA, where allele-specific expression analyses were consistent with its interaction-mediated regulation, illustrating the utility of the approach.\n\nConclusionsOur systematic experimental framework offers an alternative approach to candidate causal gene identification for variants with cell state-specific functional effects, with achievable sample sizes.

genomics↗