NeuroGeMM Research Group
Neuro-Genetics and Mouse Models
Head of Research Group: Dr Binnaz YALCIN, PhD, HDR
Tel: +33 3 80 39 66 60
Kannan M, Bayam E, Wagner C, Rinaldi B, Kretz PF, Tilly P, Roos M, McGillewie L, Bär S, Minocha S, Chevalier C, Po C, Chelly J, Mandel JL, Borgatti R, Piton A, Kinnear C, Loos B, Adams DJ, Hérault Y, Collins SC, Friant S, Godin JD and Yalcin B.
WD40-repeat 47, a microtubule-associated protein, is essential for brain development and autophagy. PNAS.Read abstract
The family of WD40-repeat (WDR) proteins is one of the largest in eukaryotes, but little is known about their function in brain development. Among 26 WDR genes assessed, we found 7 displaying a major impact in neuronal morphology when inactivated in mice. Remarkably, all seven genes showed corpus callosum defects, including thicker (Atg16l1, Coro1c, Dmxl2, and Herc1), thinner (Kif21b and Wdr89), or absent corpus callosum (Wdr47), revealing a common role for WDR genes in brain connectivity. We focused on the poorly studied WDR47 protein sharing structural homology with LIS1, which causes lissencephaly. In a dosage-dependent manner, mice lacking Wdr47 showed lethality, extensive fiber defects, microcephaly, thinner cortices, and sensory motor gating abnormalities. We showed that WDR47 shares functional characteristics with LIS1 and participates in key microtubule-mediated processes, including neural stem cell proliferation, radial migration, and growth cone dynamics. In absence of WDR47, the exhaustion of late cortical progenitors and the consequent decrease of neurogenesis together with the impaired survival of late-born neurons are likely yielding to the worsening of the microcephaly phenotype postnatally. Interestingly, the WDR47-specific C-terminal to LisH (CTLH) domain was associated with functions in autophagy described in mammals. Silencing WDR47 in hypothalamic GT1-7 neuronal cells and yeast models independently recapitulated these findings, showing conserved mechanisms. Finally, our data identified superior cervical ganglion-10 (SCG10) as an interacting partner of WDR47. Taken together, these results provide a starting point for studying the implications of WDR proteins in neuronal regulation of microtubules and autophagy.
Collins SC, Mikhaleva A, Vrcelj K, Vancollie VE, Wagner C, Demeure N, Whitley H, Kannan M, Balz R, Anthony LFE, Edwards A, Moine H, White JK, Adams DJ, Reymond A, Lelliott CJ, Webber C and Yalcin B.
Large-scale neuroanatomical study uncovers 198 gene associations in mouse brain morphogenesis.Nature Communications.Read abstract
Brain morphogenesis is an important process contributing to higher-order cognition, however our knowledge about its biological basis is largely incomplete. Here we analyze 118 neuroanatomical parameters in 1,566 mutant mouse lines and identify 198 genes whose disruptions yield NeuroAnatomical Phenotypes (NAPs), mostly affecting structures implicated in brain connectivity. Groups of functionally similar NAP genes participate in pathways involving the cytoskeleton, the cell cycle and the synapse, display distinct fetal and postnatal brain expression dynamics and importantly, their disruption can yield convergent phenotypic patterns. 17% of human unique orthologues of mouse NAP genes are known loci for cognitive dysfunction. The remaining 83% constitute a vast pool of genes newly implicated in brain architecture, providing the largest study of mouse NAP genes and pathways. This offers a complementary resource to human genetic studies and predict that many more genes could be involved in mammalian brain morphogenesis.
Simon M, Greenaway S, White J, Fuchs H, Gailus-Durner V, Sorg T, Wong W, Bedu E, Cartwright E, Dacquin R, Djebali S, Estabel J, Graw J, Ingham N, Jackson I, Lengeling A, Mandillo S, Marvel J, Meziane H, Preitner F, Puk O, Roux M, Adams D, Atkins S, Ayadi A, Becker L, Blake A, Brooker D, Cater H, Champy MF, Combe R, Danecek P, di Fenza A, Gates H, Gerdin AK, Golini E, Hancock J, Hans W, Hölter S, Hough T, Jurdic P, Keane T, Morgan H, Müller W, Neff F, Nicholson G, Pasche B, Roberson LA, Rozman J, Sanderson M, Santos L, Selloum M, Shannon C, Southwell, Tocchini-Valentini A, Vancollie V, Wells S, Westerberg H, Wurst W, Zi M, Yalcin B*, Ramirez-Solis R*, Steel K*, Mallon AM*, Hrabé de Angelis M*, Hérault Y*, Brown S*. *Co-last author.
A comparative phenotypic and genomic analysis of C57BL/6J and C57BL/6N mouse strains. Genome Biology.Read abstract
Background: The mouse inbred line C57BL/6J is widely used in mouse genetics and its genome has been incorporated into many genetic reference populations. More recently large initiatives such as the International Knockout Mouse Consortium (IKMC) are using the C57BL/6N mouse strain to generate null alleles for all mouse genes. Hence both strains are now widely used in mouse genetics studies. Here we perform a comprehensive genomic and phenotypic analysis of the two strains to identify differences that may influence their underlying genetic mechanisms. Results: We undertake genome sequence comparisons of C57BL/6J and C57BL/6N to identify SNPs, indels and structural variants, with a focus on identifying all coding variants. We annotate 34 SNPs and 2 indels that distinguish C57BL/6J and C57BL/6N coding sequences, as well as 15 structural variants that overlap a gene. In parallel we assess the comparative phenotypes of the two inbred lines utilizing the EMPReSSslim phenotyping pipeline, a broad based assessment encompassing diverse biological systems. We perform additional secondary phenotyping assessments to explore other phenotype domains and to elaborate phenotype differences identified in the primary assessment. We uncover significant phenotypic differences between the two lines, replicated across multiple centers, in a number of physiological, biochemical and behavioral systems. Conclusions: Comparison of C57BL/6J and C57BL/6N demonstrates a range of phenotypic differences that have the potential to impact upon penetrance and expressivity of mutational effects in these strains. Moreover, the sequence variants we identify provide a set of candidate genes for the phenotypic differences observed between the two strains.
Yalcin B, Wong K, Agam A, Goodson M, Keane T, Gan X, Nellåker C, Goodstadt L, Nicod J, Bhomra A, Whitley H, Cleak J, Dutton R, Mott R, Adams D, Flint J.
Sequence based characterization of structural variation in the mouse genome. Nature.Read abstract
Structural variation is widespread in mammalian genomes and is an important cause of disease, but just how abundant and important structural variants (SVs) are in shaping phenotypic variation remains unclear. Without knowing how many SVs there are, and how they arise, it is difficult to discover what they do. Combining experimental with automated analyses, we identified 711,920 SVs at 281,243 sites in the genomes of thirteen classical and four wild-derived inbred mouse strains. The majority of SVs are less than 1 kilobase in size and 98% are deletions or insertions. The breakpoints of 160,000 SVs were mapped to base pair resolution, allowing us to infer that insertion of retrotransposons causes more than half of SVs. Yet, despite their prevalence, SVs are less likely than other sequence variants to cause gene expression or quantitative phenotypic variation. We identified 24 SVs that disrupt coding exons, acting as rare variants of large effect on gene function. One-third of the genes so affected have immunological functions.
Yalcin B, Willis-Owen SA, Fullerton J, Meesaq A, Deacon RM, Rawlins JNP, Copley RR, Morris AP, Flint J, Mott R.
Genetic dissection of a behavioural quantitative trait locus shows that Rgs2 modulates anxiety in mice. Nature Genetics.Read abstract
Here we present a strategy to determine the genetic basis of variance in complex phenotypes that arise from natural, as opposed to induced, genetic variation in mice. We show that a commercially available strain of outbred mice, MF1, can be treated as an ultrafine mosaic of standard inbred strains and accordingly used to dissect a known quantitative trait locus influencing anxiety. We also show that this locus can be subdivided into three regions, one of which contains Rgs2, which encodes a regulator of G protein signaling. We then use quantitative complementation to show that Rgs2 is a quantitative trait gene. This combined genetic and functional approach should be applicable to the analysis of any quantitative trait.
2021 Jeanne M, Vuillaume ML, Ung DC, Vancollie VE, Wagner C, Collins SC, Vonwill S, Haye D, Chelloug N, Pfundt R, Kummeling J, Moizard MP, Marouillat S, Kleefstra T, Yalcin B, Laumonnier F, Toutain A. Haploinsufficiency of the HIRA gene located in the 22q11 deletion syndrome region is associated with abnormal neurodevelopment and impaired dendritic outgrowth. Hum Genet. 2021 Jan 8.
2020 Duncan AR, Vitobello A, Collins SC, Vancollie VE, Lelliott CJ, Rodan L, Shi J, Seman AR, Agolini E, Novelli A, Prontera P, Guillen Sacoto MJ, Santiago-Sim T, Trimouille A, Goizet C, Nizon M, Bruel AL, Philippe C, Grant PE, Wojcik MH, Stoler J, Genetti CA, van Dooren MF, Maas SM, Alders M, Faivre L, Sorlin A, Yoon G, Yalcin B*, Agrawal PB*. Heterozygous Variants in KDM4B Lead to Global Developmental Delay and Neuroanatomical Defects. Am J Hum Genet. 2020 Dec 3;107(6):1170-1177. *Co-corresponding author.
Liang ZS, Cimino I, Yalcin B, Raghupathy N, Vancollie VE, Ibarra-Soria X, Firth HV, Rimmington D, Farooqi IS, Lelliott CJ, Munger SC, O’Rahilly S, Ferguson-Smith AC, Coll AP, Logan DW. Trappc9 deficiency causes parent-of-origin dependent microcephaly and obesity. Plos Genetics. 2020 Sep 2;16(9):e1008916.
Milh M, Roubertoux P, Biba N, Chavany J, Spiga Ghata A, Fulachier C, Collins SC, Wagner C, Roux JC, Yalcin B, Félix MS, Molinari F, Lenck-Santini PP, Villard L. A knock-in mouse model for KCNQ2-related epileptic encephalopathy displays spontaneous generalized seizures and cognitive impairment. Epilepsia. 2020 May;61(5):868-878.
Gilet J, Ivanova E, Trofimova D, Rudolf G, Meziane H, Broix L, Drouot N, Courraud J, Skory V, Voulleminot P, Osipenko M, Bahi-Buisson N, Yalcin B, Birling MC, Hinckelmann MV, Kwok BH, Allingham JS, Chelly J. Conditional switching of KIF2A mutation provides new insights into cortical malformations pathogeny. Hum Mol Genet. 2020 Jan 10.
2019 Collins SC, Mikhaleva A, Vrcelj K, Vancollie VE, Wagner C, Demeure N, Whitley H, Kannan M, Balz R, Anthony LFE, Edwards A, Moine H, White JK, Adams DJ, Reymond A, Lelliott CJ, Webber C, Yalcin B.Large-scale neuroanatomical study uncovers 198 gene associations in mouse brain morphogenesis. Nature Communications. 2019 Aug 1;10(1):3465.
Collins SC, Uzquiano A, Selloum M, Wendling O, Gaborit M, Osipenko M, Birling MC, Yalcin B*, Francis F*. The neuroanatomy of Eml1 knockout mice, a model of subcortical heterotopia. J Anat. 2019 Sep;235(3):637-650. *Co-last author
Ivanova EL, Gilet JG, Sulimenko V, Duchon A, Rudolf G, Runge K, Collins SC, Asselin L, Broix L, Drouot N, Tilly P, Nusbaum P, Vincent A, Magnant W, Skory V, Birling MC, Pavlovic G, Godin JD, Yalcin B, Hérault Y, Dráber P, Chelly J, Hinckelmann MV. TUBG1 missense variants underlying cortical malformations disrupt neuronal locomotion and microtubule dynamics but not neurogenesis. Nature Communications. 2019 May 13;10(1):2129.
2018 Lilue J, Doran AG, Fiddes IT, Abrudan M, Armstrong J, Bennett R, Chow W, Collins J, Collins S, Czechanski A, Danecek P, Diekhans M, Dolle DD, Dunn M, Durbin R, Earl D, Ferguson-Smith A, Flicek P, Flint J, Frankish A, Fu B, Gerstein M, Gilbert J, Goodstadt L, Harrow J, Howe K, Ibarra-Soria X, Kolmogorov M, Lelliott CJ, Logan DW, Loveland J, Mathews CE, Mott R, Muir P, Nachtweide S, Navarro FCP, Odom DT, Park N, Pelan S, Pham SK, Quail M, Reinholdt L, Romoth L, Shirley L, Sisu C, Sjoberg-Herrera M, Stanke M, Steward C, Thomas M, Threadgold G, Thybert D, Torrance J, Wong K, Wood J, Yalcin B, Yang F, Adams DJ, Paten B, Keane TM. Sixteen diverse laboratory mouse reference genomes define strain-specific haplotypes and novel functional loci. Nature Genetics. 2018 Nov;50(11):1574-1583.
Collins SC, Wagner C, Gagliardi L, Kretz PF, Fischer MC, Kannan M, Yalcin B*. A method for parasagittal sectioning for neuroanatomical quantification of brain structure in the adult mouse. Current Protocols in Mouse Biology. 2018
2017 Kannan M, Bayam E, Wagner C, Rinaldi B, Kretz PF, Tilly P, Roos M, McGillewie L, Bär S, Minocha S, Chevalier C, Po C, Chelly J, Mandel JL, Borgatti R, Piton A, Kinnear C, Loos B, Adams DJ, Hérault Y, Collins SC, Friant S, Godin JD, Yalcin B. WD40-repeat 47, a microtubule-associated protein, is essential for brain development and autophagy. Proc Natl Acad Sci U S A. 2017 Oct 31;114(44):E9308-E9317.
Loviglio MN, Arbogast T, Jønch AE, Collins SC, Popadin K, Bonnet CS, Giannuzzi G, Maillard AM, Jacquemont S; 16p11.2 Consortium, Yalcin B, Katsanis N, Golzio C, Reymond A. The Immune Signaling Adaptor LAT Contributes to the Neuroanatomical Phenotype of 16p11.2 BP2-BP3 CNVs. Am J Hum Genet. 2017 Oct 5;101(4):564-577.
van der Werf IM, Van Dam D, Missault S, Yalcin B, De Deyn PP, Vandeweyer G, Kooy RF. Behavioural characterization of AnkyrinG deficient mice, a model for ANK3 related disorders. Behav Brain Res. 2017 Jun 15;328:218-226
2016 Mikhaleva A, Kannan M, Wagner C, Yalcin B*. High-throughput morphological phenotyping of the mouse brain. Current Protocols in Mouse Biology. 2016. *Invited
2014 Keane TM, Wong K, Adams DJ, Flint J, Reymond A, Yalcin B*. Identification of structural variation in mouse genomes. Frontiers in Genetics. 2014, 5:19. *Invited
2013 Simon M, Greenaway S, White J, Fuchs H, Gailus-Durner V, Sorg T, Wong W, Bedu E, Cartwright E, Dacquin R, Djebali S, Estabel J, Graw J, Ingham N, Jackson I, Lengeling A, Mandillo S, Marvel J, Meziane H, Preitner F, Puk O, Roux M, Adams D, Atkins S, Ayadi A, Becker L, Blake A, Brooker D, Cater H, Champy MF, Combe R, Danecek P, di Fenza A, Gates H, Gerdin AK, Golini E, Hancock J, Hans W, Hölter S, Hough T, Jurdic P, Keane T, Morgan H, Müller W, Neff F, Nicholson G, Pasche B, Roberson LA, Rozman J, Sanderson M, Santos L, Selloum M, Shannon C, Southwell, Tocchini-Valentini A, Vancollie V, Wells S, Westerberg H, Wurst W, Zi M, Yalcin B*, Ramirez-Solis R*, Steel K*, Mallon AM*, Hrabé de Angelis M*, Hérault Y*, Brown S*. A comparative phenotypic and genomic analysis of C57BL/6J and C57BL/6N mouse strains. Genome Biology. 2013, 14(7):R82. *Co-last author
White JK, Gerdin AK, Karp NA, Ryder E, Buljan M, Bussell JN, Salisbury J, Clare S, Ingham NJ, Podrini C, Houghton R, Estabel J, Bottomley JR, Melvin DG, Sunter D, Adams NC, Yalcin B, Sanger Institute Mouse Genetics Project, Tannahill D, Logan DW, Macarthur DG, Flint J, Mahajan VB, Tsang SH, Smyth I, Watt FM, Skarnes WC, Dougan G, Adams DJ, Ramirez-Solis R, Bradley A, Steel KP. Genome-wide generation and systematic phenotyping of knockout mice reveals new roles for many genes. Cell. 2013, 154(2) :452-64.
2012 Yalcin B*, Wong K, Bhomra A, Goodson M, Keane T, Adams D, Flint J. The fine-scale architecture of structural variants in 17 mouse genomes. Genome Biology. 2012, 13(3):R18. *Corresponding author
Nellåker C, Keane T, Yalcin B, Wong K, Agam A, Belgard G, Flint J, Adams D, Frankel W, Ponting C. The genomic landscape shaped by selection on transposable elements across 18 mouse strains. Genome Biology. 2012, 13(6):R45.
Collaborative Cross Consortium. The genome architecture of the Collaborative Cross mouse genetic reference population. Genetics. 2012, 190(2):389-401.
Yalcin B*, Adams D, Flint J, Keane T. Next-generation sequencing of experimental mouse strains. Mammalian Genome. 2012, 23(9-10):490-8. *Invited and corresponding author
Yalcin B*, Flint J. Association studies in outbred mice in a new era of full-genome sequencing. Mammalian Genome. 2012, 23(9-10):719-26. * Invited and corresponding author
2011 Yalcin B, Wong K, Agam A, Goodson M, Keane T, Gan X, Nellåker C, Goodstadt L, Nicod J, Bhomra A, Hernandez-Pliego P, Whitley H, Cleak J, Dutton R, Mott R, Adams D, Flint J. Sequence based characterization of structural variation in the mouse genome. Nature. 2011, 477(7364):326-9.
Keane T, Goodstadt L, Danecek P, White M, Wong K, Yalcin B, Heger A, Agam A, Slater G, Goodson M, Furotte N, Eskin E, Nellåker C, Whitley H, Cleak J, Janowitz D, Hernandez-Pliego P, Edwards A, Belgard G, Oliver P, McIntyre R, Bhomra A, Nicod J, Gan X, Yuan W, van der Weyden L, Steward C, Balasubramaniam S, Stalker J, Mott R, Durbin R, Jackson I, Czechanski, Assuncao J, Donahue L, Reinholdt, Payseur B, Ponting C, Birney E, Flint J, Adams D. Mouse genomic variation and its effect on phenotypes and gene regulation. Nature. 2011, 477(7364):289-94.
Durrant C, Tayem H, Yalcin B, Cleak J, Goodstadt L, Pardo-Manuel de Villena F, Mott R, Iraqi F. Collaborative Cross mice and their power to map host susceptibility to Aspergillus fumigatus infection. Genome Research. 2011, 21(8):1239-1248.
2010 Yalcin B, Nicod J, Bhomra A, Davidson S, Cleak J, Farinelli L, Østerås M, Yuan W, Whitley A, Gan X, Goodson M, Klenerman P, Satpathy A, Benoist C, Adams DJ, Mott R, Flint J. Commercially available outbred mice for genome-wide association studies. Plos Genetics. 2010, 2;6(9).
Agam A*, Yalcin B*, Bhomra A, Cubin M, Webber C, Holmes C, Flint J, Mott R. Elusive copy number variation in the mouse genome. Plos One. 2010, 5(9). *Co-first author
2009 Huang G, Shifman S, Valdar W, Johannesson M, Yalcin B, Taylor MS, Taylor JM, Mott R, Flint J. High resolution mapping of expression QTLs in heterogeneous stock mice in multiple tissues. Genome Research. 2009, 19: 1133-1140.
2008 Munafò MR, Yalcin B, Willis-Owen SA, Flint J. Association of the dopamine D4 receptor (DRD4) gene and approach-related personality traits: meta-analysis and new data. Biological Psychiatry. 2008, 63: 197-206.
Fullerton J, Willis-Owen SA, Yalcin B, Shifman S, Copley RR, Miller S, Bhomra A, Davidson S, Oliver PL, Mott R, Flint J. Human-mouse quantitative trait locus concordance and the dissection of a human neuroticism locus. Biological Psychiatry. 2008, 63: 874-883.
2005 Yalcin B, Flint J, Mott R. Using progenitor strain information to identify quantitative trait nucleotides in outbred mice. Genetics. 2005, 171: 673-681.
2004 Yalcin B, Willis-Owen SA, Fullerton J, Meesaq A, Deacon RM, Rawlins JNP, Copley RR, Morris AP, Flint J, Mott R. Genetic dissection of a behavioural quantitative trait locus shows that Rgs2 modulates anxiety in mice. Nature Genetics. 2004, 36: 1197-1202.
Yalcin B, Fullerton J, Miller S, Keays DA, Brady SA, Bhomra A, Jefferson A, Volpi E, Copley RR, Flint J, Mott R. Unexpected complexity in the haplotypes of commonly used inbred strains of laboratory mice.Proc Natl Acad Sci U S A. 2004, 101: 9734-9739.