A selected list of publications from the Yalcin’s Group:
Szpak M$, Collins SC$, Li Y, Liu X, Ayub Q, Fischer MC, Vancollie VE, Lelliott CJ, Xue Y, Yalcin B*, Yang H, Tyler-Smith C*. $Co-first *Co-last authors. A positively-selected MAGEE2 LoF allele is associated with sexual dimorphism in human brain size, and shows similar phenotypes in Magee2 null mice. Molecular Biology and Evolution. 2021
A nonsense allele at rs1343879 in human MAGEE2 on chromosome X has previously been reported as a strong candidate for positive selection in East Asia. This premature stop codon causing ∼80% protein truncation is characterized by a striking geographical pattern of high population differentiation: common in Asia and the Americas (up to 84% in the 1000 Genomes Project East Asians) but rare elsewhere. Here, we generated a Magee2 mouse knockout mimicking the human loss-of-function mutation to study its functional consequences. The Magee2 null mice did not exhibit gross abnormalities apart from enlarged brain structures (13% increased total brain area, P = 0.0022) in hemizygous males. The area of the granular retrosplenial cortex responsible for memory, navigation and spatial information processing was the most severely affected, exhibiting an enlargement of 34% (P = 3.4×10-6). The brain size in homozygous females showed the opposite trend of reduced brain size, although this did not reach statistical significance. With these insights, we performed human association analyses between brain size measurements and rs1343879 genotypes in 141 Chinese volunteers with brain MRI scans, replicating the sexual dimorphism seen in the knockout mouse model. The derived stop gain allele was significantly associated with a larger volume of grey matter in males (P = 0.00094), and smaller volumes of grey (P = 0.00021) and white (P = 0.0015) matter in females. It is unclear whether or not the observed neuroanatomical phenotypes affect behaviour or cognition, but it might have been the driving force underlying the positive selection in humans.
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. 2019
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.
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. 2017
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.
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. 2013
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. 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. 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.
Szpak M, Collins SC, Li Y, Liu X, Ayub Q, Fischer MC, Vancollie VE, Lelliott CJ, Xue Y, Yalcin B*, Yang H, Tyler-Smith C*. A positively-selected MAGEE2 LoF allele is associated with sexual dimorphism in human brain size, and shows similar phenotypes in Magee2 null mice. Molecular Biology and Evolution. *Co-last author
Baud A, Casale FP, Barkley-Levenson AM, Farhadi N, Montillot C, Yalcin B, Nicod J, Palmer AA, Stegle O. Dissecting indirect genetic effects from peers in laboratory mice. Genome Biology.
Voisin N, Schnur RE, Douzgou S, Hiatt SM, Rustad CF, Brown NJ, Earl DL, Keren B, Levchenko O, Geuer S, Verheyen S, Johnson D, Zarate YA, Hančárová M, Amor DJ, Bebin EM, Blatterer J, Brusco A, Cappuccio G, Charrow J, Chatron N, Cooper GM, Courtin T, Dadali E, Delafontaine J, Del Giudice E, Doco M, Douglas G, Eisenkölbl A, Funari T, Giannuzzi G, Gruber-Sedlmayr U, Guex N, Heron D, Holla ØL, Hurst ACE, Juusola J, Kronn D, Lavrov A, Lee C, Lorrain S, Merckoll E, Mikhaleva A, Norman J, Pradervand S, Prchalová D, Rhodes L, Sanders VR, Sedláček Z, Seebacher HA, Sellars EA, Sirchia F, Takenouchi T, Tanaka AJ, Taska-Tench H, Tønne E, Tveten K, Vitiello G, Vlčková M, Uehara T, Nava C, Yalcin B, Kosaki K, Donnai D, Mundlos S, Brunetti-Pierri N, Chung WK, Reymond A. Variants in the degron of AFF3 are associated with intellectual disability, mesomelic dysplasia, horseshoe kidney, and epileptic encephalopathy. Am J Hum Genet.
Niewiadomska-Cimicka A, Doussau F, Perot JB, Roux MJ, Keime C, Hache A, Piguet F, Novati A, Weber C, Yalcin B, Meziane H, Champy MF, Grandgirard E, Karam A, Messaddeq N, Eisenmann A, Brouillet E, Nguyen HHP, Flament J, Isope P, Trottier Y. SCA7 Mouse Cerebellar Pathology Reveals Preferential Downregulation of Key Purkinje Cell-Identity Genes and Shared Disease Signature with SCA1 and SCA2. Journal of Neuroscience.
Bonfante B, Faux P, Navarro N, Mendoza-Revilla J, Dubied M, Montillot C, Wentworth E, Poloni L, Varón-González C, Jones P, Xiong Z, Fuentes-Guajardo M, Palmal S, Chacón-Duque JC, Hurtado M, Villegas V, Granja V, Jaramillo C, Arias W, Barquera R, Everardo-Martínez P, Sánchez-Quinto M, Gómez-Valdés J, Villamil-Ramírez H, Silva de Cerqueira CC, Hünemeier T, Ramallo V, Liu F, Weinberg SM, Shaffer JR, Stergiakouli E, Howe LJ, Hysi PG, Spector TD, Gonzalez-José R, Schüler-Faccini L, Bortolini MC, Acuña-Alonzo V, Canizales-Quinteros S, Gallo C, Poletti G, Bedoya G, Rothhammer F, Thauvin-Robinet C, Faivre L, Costedoat C, Balding D, Cox T, Kayser M, Duplomb L, Yalcin B, Cotney J, Adhikari K, Ruiz-Linares A. A GWAS in Latin Americans identifies novel face shape loci, implicating VPS13B and a Denisovan introgressed region in facial variation. Science Advances.
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. Human Genetics.
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. *Co-last 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.
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.
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.
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.
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. Journal of Anatomy. *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.
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.
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. *Invited
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.
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.
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. Behavioral Brain Research.
Mikhaleva A, Kannan M, Wagner C, Yalcin B*. High-throughput morphological phenotyping of the mouse brain. Current Protocols in Mouse Biology. *Invited
Keane TM, Wong K, Adams DJ, Flint J, Reymond A, Yalcin B*. Identification of structural variation in mouse genomes. Frontiers in Genetics. *Invited
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. *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.
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. *Correspondence
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.
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. *Invited and correspondence
Yalcin B*, Flint J. Association studies in outbred mice in a new era of full-genome sequencing. Mammalian Genome. *Invited and correspondence
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.
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.
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.
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.
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. *Co-first author
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.
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.
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.
Yalcin B, Flint J, Mott R. Using progenitor strain information to identify quantitative trait nucleotides in outbred mice. Genetics.
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.
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.