The landscape of expression and alternative splicing variation across human traits

Understanding the consequences of individual transcriptome variation is fundamental to deciphering human biology and disease. We implement a statistical framework to quantify the contributions of 21 individual traits as drivers of gene expression and alternative splicing variation across 46 human tissues and 781 individuals from the Genotype-Tissue Expression project. We demonstrate that ancestry, sex, age, and BMI make additive and tissue-specific contributions to expression variability, whereas interactions are rare. Variation in splicing is dominated by ancestry and is under genetic control in most tissues, with ribosomal proteins showing a strong enrichment of tissue-shared splicing events. Our analyses reveal a systemic contribution of types 1 and 2 diabetes to tissue transcriptome variation with the strongest signal in the nerve, where histopathology image analysis identifies novel genes related to diabetic neuropathy. Our multi-tissue and multi-trait approach provides an extensive characterization of the main drivers of human transcriptome variation in health and disease.This study was funded by the HumTranscriptom project with reference PID2019-107937GA-I00. R.G.-P. was supported by a Juan de la Cierva fellowship (FJC2020-044119-I) funded by MCIN/AEI/10.13039/501100011033 and ‘‘European Union NextGenerationEU/PRTR.’’ J.M.R. was supported by a predoctoral fellowship from ‘‘la Caixa’’ Foundation (ID 100010434) with code LCF/BQ/DR22/11950022. A.R.-C. was supported by a Formación Personal Investigador (FPI) fellowship (PRE2019-090193) funded by MCIN/AEI. R.C.-G. was supported by an FPI fellowship (PRE2020-092510) funded by MCIN/AEI. M.M. was supported by a Ramon y Cajal fellowship (RYC-2017-22249).Peer ReviewedPostprint (published version

Fragmentary Understanding of Memory

My thesis argues that memory resembles navigation by fragments, as proposed in [1]. To relate to it, imagine you are in Paris and you already know quite well the neighbourhood of where you are staying. Now, it is easy to get to the Eiffel Tower: you may need some help with an overall direction, but once you follow it, it does not really matter how exactly, very soon you will see the Tower and you will nd your way to it. When you get closer you will remember the immediate surroundings of the Tower and how to nd the nearest coffee place. Similarly from there you can get to Notre Dame: now you may just follow the river, it is one-way and you may only remember just a couple of spots along the way, but near the Cathedral you recognize every pigeon. Here the remembered fragments are the two landmarks, their neighbourhood and the river, to some extent. Keep this in mind. I prepared a guided tour for you, where the fragments I learned to navigate through are memory phenomena that can be studied from a point of view of navigation by fragments. Pick a sustainable vehicle, I suggest a sailing boat as it must have the right speed, or you may imagine this trip as cycling uphill (as I certainly felt it), and follow my thoughts. We start with the hippocampus and its relation to memory and navigation. We discuss how the discovery of spatially selective cells there led to study memory systems in our brain as attractor neural networks, what fragmentary knowledge about the representation of space could be learnt from the hippocampus and the open questions that remain. Just across a bridge, in Chapter 2, we will attempt to answer some of those questions, studying a mathematical model of an attractor neural network in CA3. We will expand our knowledge about the quasi-continuous maps our model forms for multiple sample environments, their storage and their usage. We will argue that CA3 network storage can in fact be thought of as a fragment assembly. We must take a series of one-way turns to reach some understanding of how human recall relates to virtual rat navigation, but I will be your guide. In chapters 3 and 4 we will discuss, using free recall as a model example, how human memory, too, can be thought of as navigation by fragments. We will present a series of experiments and simulations of a Potts network that together point at the semi-random nature of human recall. We suggest that when given a plain environment to learn - a hexagonal grid on a screen, as an empty box for a rat in a lab, human participants tend to memorize locations on the screen by `seeing' there various familiar fragments. And the more restrictive the memorization task is, the least they can reach these attractive patterns. We will discuss how common biases and unanimity across participants in fragment activation can be predictive of human recall capacity. Finally, we will briefly visit Milan of Mind Wandering and Rome of Remembering Poetry. We will argue that, despite being seemingly (and luckily) far from each other, both of these places-processes have in common their functional reliance on fragmentary schemata. First, we will propose an experiment that aims at quantifying the effect of recently acquired episodic schemata on mind wandering in participants with a lesion to vmPFC and in their healthy controls. Separately, we will suggest a mechanism of selective involvement of poetic meter variables as schemata helping remember non-words in non-poems. In the end we will gather to review the pictures from the journey and discuss the takeaways. Let's go

Meter and memory

This study aimed at investigating the patterns of meter as a cognitive schema which aid verbal memory. We focused on classical Italian poetry and of three components in particular: rhyme, verse length and accent

In poetry, if meter has to help memory, it takes its time [version 2; peer review: 2 approved, 2 not approved]

To test the idea that poetic meter emerged as a cognitive schema to aid verbal memory, we focused on classical Italian poetry and on three components of meter: rhyme, accent, and verse length. Meaningless poems were generated by introducing prosody-invariant non-words into passages from Dante’s Divina Commedia and Ariosto’s Orlando Furioso. We then ablated rhymes, modified accent patterns, or altered the number of syllables. The resulting versions of each non-poem were presented to Italian native speakers, who were then asked to retrieve three target non-words. Surprisingly, we found that the integrity of Dante’s meter has no significant effect on memory performance. With Ariosto, instead, removing each component downgrades memory proportionally to its contribution to perceived metric plausibility. Counterintuitively, the fully metric versions required longer reaction times, implying that activating metric schemata involves a cognitive cost. Within schema theories, this finding provides evidence for high-level interactions between procedural and episodic memory

In poetry, if meter has to help memory, it takes its time

To test the idea that poetic meter emerged as a cognitive schema to aid verbal memory, we focused on classical Italian poetry and on three components of meter: rhyme, accent, and verse length. Meaningless poems were generated by introducing prosody-invariant non-words into passages from Dante's Divina Commedia and Ariosto's Orlando Furioso. We then ablated rhymes, modified accent patterns, or altered the number of syllables. The resulting versions of each non-poem were presented to Italian native speakers, who were then asked to retrieve three target non-words. Surprisingly, we found that the integrity of Dante's meter has no significant effect on memory performance. With Ariosto, instead, removing each component downgrades memory proportionally to its contribution to perceived metric plausibility. Counterintuitively, the fully metric versions required longer reaction times, implying that activating metric schemata involves a cognitive cost. Within schema theories, this finding provides evidence for high-level interactions between procedural and episodic memory

Latching dynamics as a basis for short-term recall

We discuss simple models for the transient storage in short-term memory of cortical patterns of activity, all based on the notion that their recall exploits the natural tendency of the cortex to hop from state to state—latching dynamics. We show that in one such model, and in simple spatial memory tasks we have given to human subjects, short-term memory can be limited to similar low capacity by interference effects, in tasks terminated by errors, and can exhibit similar sublinear scaling, when errors are overlooked. The same mechanism can drive serial recall if combined with weak order-encoding plasticity. Finally, even when storing randomly correlated patterns of activity the network demonstrates correlation-driven latching waves, which are reflected at the outer extremes of pattern space

Information parity increases on functional brain networks under influence of a psychedelic substance

The physical basis of consciousness is one of the most intriguing open questions that contemporary science aims to solve. By approaching the brain as an interactive information system, complex network theory has greatly contributed to understand brain process in different states of mind. We study a non-ordinary state of mind by comparing resting-state functional brain networks of individuals in two different conditions: before and after the ingestion of the psychedelic brew Ayahuasca. In order to quantify the functional, statistical symmetries between brain region connectivity, we calculate the pairwise information parity of the functional brain networks. Unlike the usual approach to quantitative network analysis that considers only local or global scales, information parity instead quantifies pairwise statistical similarities over the entire network structure. We find an increase in the average information parity on brain networks of individuals under psychedelic influences. Notably, the information parity between regions from the limbic system and frontal cortex is consistently higher for all the individuals while under the psychedelic influence. These findings suggest that the resemblance of statistical influences between pair of brain regions activities tends to increase under Ayahuasca effects. This could be interpreted as a mechanism to maintain the network functional resilience

The landscape of expression and alternative splicing variation across human traits

Understanding the consequences of individual transcriptome variation is fundamental to deciphering human biology and disease. We implement a statistical framework to quantify the contributions of 21 individual traits as drivers of gene expression and alternative splicing variation across 46 human tissues and 781 individuals from the Genotype-Tissue Expression project. We demonstrate that ancestry, sex, age, and BMI make additive and tissue-specific contributions to expression variability, whereas interactions are rare. Variation in splicing is dominated by ancestry and is under genetic control in most tissues, with ribosomal proteins showing a strong enrichment of tissue-shared splicing events. Our analyses reveal a systemic contribution of types 1 and 2 diabetes to tissue transcriptome variation with the strongest signal in the nerve, where histopathology image analysis identifies novel genes related to diabetic neuropathy. Our multi-tissue and multi-trait approach provides an extensive characterization of the main drivers of human transcriptome variation in health and disease.This study was funded by the HumTranscriptom project with reference PID2019-107937GA-I00. R.G.-P. was supported by a Juan de la Cierva fellowship (FJC2020-044119-I) funded by MCIN/AEI/10.13039/501100011033 and “European Union NextGenerationEU/PRTR.” J.M.R. was supported by a predoctoral fellowship from “la Caixa” Foundation (ID 100010434) with code LCF/BQ/DR22/11950022. A.R.-C. was supported by a Formación Personal Investigador (FPI) fellowship (PRE2019-090193) funded by MCIN/AEI. R.C.-G. was supported by an FPI fellowship (PRE2020-092510) funded by MCIN/AEI. M.M. was supported by a Ramon y Cajal fellowship (RYC-2017-22249). Figures 4A and S1A and the graphical abstract were created with BioRender.com. We thank the donors and their families for their generous gifts of organ donation for transplantation and tissue donations for the GTEx research project and the GTEx consortium members