Recent CIG publications Archive


Nat Ecol Evol.: auth.: group Benton & T.Auer

Nat Ecol Evol. 2022 Sep;6(9):1343-1353. doi: 10.1038/s41559-022-01830-y. Epub 2022 Jul 21.

Copy number changes in co-expressed odorant receptor genes enable selection for sensory differences in drosophilid species

Thomas O Auer # 1Raquel Álvarez-Ocaña # 1Steeve Cruchet 1Richard Benton 1J Roman Arguello 2 3


Despite numerous examples of chemoreceptor gene family expansions and contractions, how these relate to modifications in the sensory neuron populations in which they are expressed remains unclear. Drosophila melanogaster’s odorant receptor (Or) family is ideal for addressing this question because most Ors are expressed in distinct olfactory sensory neuron (OSN) types. Between-species changes in Or copy number may therefore indicate increases or reductions in the number of OSN populations. Here we investigated the Or67a subfamily, which exhibits copy number variation in D. melanogaster and its closest relatives: D. simulans, D. sechellia and D. mauritiana. These species’ common ancestor had three Or67a paralogues that had already diverged adaptively. Following speciation, two Or67a paralogues were lost independently in D. melanogaster and D. sechellia, with ongoing positive selection shaping the intact genes. Unexpectedly, the functionally diverged Or67a paralogues in D. simulans are co-expressed in a single neuron population, which projects to a glomerulus homologous to that innervated by Or67a neurons in D. melanogaster. Thus, while sensory pathway neuroanatomy is conserved, independent selection on co-expressed receptors has contributed to species-specific peripheral coding. This work reveals a type of adaptive change largely overlooked for olfactory evolution, raising the possibility that similar processes influence other cases of insect Or co-expression.


Trends Endocrinol Metab.: co-auth.: W.Wahli

Trends Endocrinol Metab. 2022 Sep 20;S1043-2760(22)00163-1. doi: 10.1016/j.tem.2022.08.004. Online ahead of print.

Knocking on GDF15’s door for the treatment of type 2 diabetes mellitus

David Aguilar-Recarte 1Emma Barroso 1Xavier Palomer 1Walter Wahli 2Manuel Vázquez-Carrera 3


Although a large number of drugs are available for the treatment of type 2 diabetes mellitus (T2DM), many patients do not achieve adequate disease control despite adhering to medication. Recent findings indicate that the pharmacological modulation of the stress-induced cytokine growth differentiation factor 15 (GDF15) shows promise for the treatment of T2DM. GDF15 suppresses appetite and reduces inflammation, increases thermogenesis and lipid catabolism, sustains AMP-activated protein kinase (AMPK) activity, and ameliorates insulin resistance and hepatic steatosis. In addition, circulating GDF15 levels are elevated in response to several antidiabetic drugs, including metformin, with GDF15 mediating some of their effects. Here, we review the mechanistic insights into the beneficial effects of recently explored therapeutic approaches that target GDF15 for the treatment of T2DM.

Keywords: AMPK; GFRAL; NAFLD; inflammation; insulin resistance; myokine.


J Chem Neuroanat.: auth.: S.Geller (group Fajas)

J Chem Neuroanat. 2022 Sep 1;125:102149. doi: 10.1016/j.jchemneu.2022.102149. 

The great migration: How glial cells could regulate GnRH neuron development and shape adult reproductive life

Anne H Duittoz 1Yves Tillet 1Sarah Geller 2


In mammals, reproductive function is under the control of hypothalamic neurons named Gonadotropin-Releasing Hormone (GnRH) neurons. These neurons migrate from the olfactory placode to the brain, during embryonic development. For the past 40 years, these neurons have been considered an example of tangential migration, i.e., dependent on the olfactory/vomeronasal/terminal nerves. Numerous studies have highlighted the factors involved in the migration of these neurons but thus far overlooked the cellular microenvironment that produces them. Many of these factors are dysregulated in hypogonadotropic hypogonadism, resulting in subfertility/infertility. Nevertheless, over the past ten years, several papers have reported the influence of glial cells (named olfactory ensheathing cells [OECs]) in the migration and differentiation of GnRH neurons. This review will describe the atypical origins, migration, and differentiation of these neurons, focusing on the latest discoveries. There will be a more specific discussion on the involvement of OECs in the development of GnRH neurons, during embryonic and perinatal life; as well as on their potential implication in the development of congenital or idiopathic hypogonadotropic hypogonadism (such as Kallmann syndrome).

Keywords: Glia; GnRH; HHG; Hypothalamus; LHRH; Neural crest; Olfactory ensheathing cells; Olfactory placode; Polycystic syndrome.


Hum Mol Genet.: co-auth.: group Reymond

Hum Mol Genet. 2022 Sep 6;ddac225. doi: 10.1093/hmg/ddac225. Online ahead of print.

Germline homozygous missense DEPDC5 variants cause severe refractory early-onset epilepsy, macrocephaly and bilateral polymicrogyria

Athina Ververi 1 2Sara Zagaglia 3 4Lara Menzies 1Julia Baptista 5Richard Caswell 6Stephanie Baulac 7Sian Ellard 5Sally Lynch 8 9Genomics England Research ConsortiumThomas S Jacques 10 11Maninder Singh Chawla 12Martin Heier 13Mari Ann Kulseth 14Inger-Lise Mero 14Anne Katrine Våtevik 15Ichraf Kraoua 16Hanene Ben Rhouma 16Thouraya Ben Younes 16Zouhour Miladi 16Ilhem Ben Youssef Turki 16Wendy D Jones 1Emma Clement 1Christin Eltze 17Kshitij Mankad 18Ashirwad Merve 11Jennifer Parker 19Bethan Hoskins 19Ronit Pressler 20Sniya Sudhakar 18Catherine DeVile 17Tessa Homfray 21Marios Kaliakatsos 17Prab Prabhakar Ponnudas 17Robert Robinson 17Sara Margrete Bøen Keim 14Imen Habibi 22Alexandre Reymond 22Sanjay M Sisodiya 3 4Jane A Hurst 1


Purpose: DEPDC5 (DEP Domain-Containing Protein 5) encodes an inhibitory component of the mTOR pathway and is commonly implicated in sporadic and familial focal epilepsies, both non-lesional and in association with focal cortical dysplasia. Germline pathogenic variants are typically heterozygous and inactivating. We describe a novel phenotype caused by germline biallelic missense variants in DEPDC5.

Methods: Cases were identified clinically. Available records, including MRI and EEG, were reviewed. Genetic testing was performed by whole exome and whole genome sequencing and cascade screening. In addition, immunohistochemistry was performed on skin biopsy.

Results: The phenotype was identified in nine children, eight of which are described in detail herein. Six of the children were of Irish Traveller, two of Tunisian and one of Lebanese origin. The Irish Traveller children shared the same DEPDC5 germline homozygous missense variant (p.Thr337Arg), whereas the Lebanese and Tunisian children shared a different germline homozygous variant (p.Arg806Cys). Consistent phenotypic features included extensive bilateral polymicrogyria, congenital macrocephaly and early-onset refractory epilepsy, in keeping with other mTOR-opathies. Eye and cardiac involvement, and severe neutropenia, were also observed in one or more patients. Five of the children died in infancy or childhood, the other four are currently aged between five months and six years. Skin biopsy immunohistochemistry was supportive of hyperactivation of the mTOR pathway.

Discussion: The clinical, histopathological and genetic evidence supports a causal role for the homozygous DEPDC5 variants, expanding our understanding of the biology of this gene.


Nucleic Acids Res.: co-auth.: A.Reymond

Nucleic Acids Res. 2022 Sep 21;gkac779. doi: 10.1093/nar/gkac779. Online ahead of print.

A mitochondria-specific mutational signature of aging: increased rate of A > G substitutions on the heavy strand

Alina G Mikhailova 1 2Alina A Mikhailova 1Kristina Ushakova 1Evgeny O Tretiakov 1 3Dmitrii Iliushchenko 1Victor Shamansky 1Valeria Lobanova 1Ivan Kozenkov 1Bogdan Efimenko 1Andrey A Yurchenko 4Elena Kozenkova 5Evgeny M Zdobnov 6 7Vsevolod Makeev 2 8Valerian Yurov 5Masashi Tanaka 9Irina Gostimskaya 10Zoe Fleischmann 11Sofia Annis 11Melissa Franco 11Kevin Wasko 11Stepan Denisov 1 12Wolfram S Kunz 13Dmitry Knorre 14Ilya Mazunin 15 16 17Sergey Nikolaev 4Jacques Fellay 7 18Alexandre Reymond 19Konstantin Khrapko 11Konstantin Gunbin 1 20Konstantin Popadin 1 7 18


The mutational spectrum of the mitochondrial DNA (mtDNA) does not resemble any of the known mutational signatures of the nuclear genome and variation in mtDNA mutational spectra between different organisms is still incomprehensible. Since mitochondria are responsible for aerobic respiration, it is expected that mtDNA mutational spectrum is affected by oxidative damage. Assuming that oxidative damage increases with age, we analyse mtDNA mutagenesis of different species in regards to their generation length. Analysing, (i) dozens of thousands of somatic mtDNA mutations in samples of different ages (ii) 70053 polymorphic synonymous mtDNA substitutions reconstructed in 424 mammalian species with different generation lengths and (iii) synonymous nucleotide content of 650 complete mitochondrial genomes of mammalian species we observed that the frequency of AH > GH substitutions (H: heavy strand notation) is twice bigger in species with high versus low generation length making their mtDNA more AH poor and GH rich. Considering that AH > GH substitutions are also sensitive to the time spent single-stranded (TSSS) during asynchronous mtDNA replication we demonstrated that AH > GH substitution rate is a function of both species-specific generation length and position-specific TSSS. We propose that AH > GH is a mitochondria-specific signature of oxidative damage associated with both aging and TSSS.


Genome Med.: auth.: group Reymond

Genome Med. 2022 Aug 11;14(1):89. doi: 10.1186/s13073-022-01088-w.

Limited evidence for blood eQTLs in human sexual dimorphism

Eleonora Porcu 1 2 3Annique Claringbould 4 5Antoine Weihs 6Kaido Lepik 7 8BIOS ConsortiumTom G Richardson 9 10Uwe Völker 11 12Federico A Santoni 13 14Alexander Teumer 12 15Lude Franke 4Alexandre Reymond # 16Zoltán Kutalik # 17 18 19


Background: The genetic underpinning of sexual dimorphism is very poorly understood. The prevalence of many diseases differs between men and women, which could be in part caused by sex-specific genetic effects. Nevertheless, only a few published genome-wide association studies (GWAS) were performed separately in each sex. The reported enrichment of expression quantitative trait loci (eQTLs) among GWAS-associated SNPs suggests a potential role of sex-specific eQTLs in the sex-specific genetic mechanism underlying complex traits.

Methods: To explore this scenario, we combined sex-specific whole blood RNA-seq eQTL data from 3447 European individuals included in BIOS Consortium and GWAS data from UK Biobank. Next, to test the presence of sex-biased causal effect of gene expression on complex traits, we performed sex-specific transcriptome-wide Mendelian randomization (TWMR) analyses on the two most sexually dimorphic traits, waist-to-hip ratio (WHR) and testosterone levels. Finally, we performed power analysis to calculate the GWAS sample size needed to observe sex-specific trait associations driven by sex-biased eQTLs.

Results: Among 9 million SNP-gene pairs showing sex-combined associations, we found 18 genes with significant sex-biased cis-eQTLs (FDR 5%). Our phenome-wide association study of the 18 top sex-biased eQTLs on >700 traits unraveled that these eQTLs do not systematically translate into detectable sex-biased trait-associations. In addition, we observed that sex-specific causal effects of gene expression on complex traits are not driven by sex-specific eQTLs. Power analyses using real eQTL- and causal-effect sizes showed that millions of samples would be necessary to observe sex-biased trait associations that are fully driven by sex-biased cis-eQTLs. Compensatory effects may further hamper their detection.

Conclusions: Our results suggest that sex-specific eQTLs in whole blood do not translate to detectable sex-specific trait associations of complex diseases, and vice versa that the observed sex-specific trait associations cannot be explained by sex-specific eQTLs.