Sex chromosome complement contributes to sex differences in disease phenotypes

Transcription

1 Sex chromosome complement contributes to sex differences in disease phenotypes Art Arnold Dept Integrative Biology & Physiology Director, Lab of Neuroendocrinology Brain Research Institute UCLA UCLA

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3 Four points 1. Using Four Core Genotypes and XY* mouse models, we compare mice with the same gonad type but with different sex chromosomes, measuring physiology and disease. 2. Sex chromosome complement contributes to sex differences (XX = XY, XO = XX). / / 3. The number of X chromosomes contributes to sex differences: obesity, cardiac ischemic / reperfusion, multiple sclerosis, neural tube closure defect, Alzheimers models. 4. Sex biasing mechanisms sometimes counteract each other (compensation).

4 Basic Question The physician wants to identify and enhance sex-biased factors that protect from disease. What (categories of) biological factors cause sex differences in phenotype? Where do we look for sex-biasing factors? What s the conceptual framework for studying sex differences?

5 XY vs. XX At the genetic level, all sex differences result from X and Y imbalance* Aren t autosomal genes involved in sex differences? X Y *in species with heteromorphic sex chromosomes

6 20 th Century Central Dogma XY vs. XX Gonads Sex Determination (first, genetic) Sex Differences in Non-Gonadal Traits Sexual Differentiation (second, hormonal)

7 XY vs. XX Genetic level: All sex differences result from X and Y imbalance Gonadal Sry in male Non-gonadal Unequal expression of X and Y genes including Sry Hormonal Organizational Effects Hormonal Activational Effects Sex Chromosome Effects Three classes of proximate factors causing sex differences in phenotype

8 XY vs. XX Genetic level: All sex differences result from X and Y imbalance Gonadal Sry in male Non-gonadal Unequal expression of X and Y genes including Sry Hormonal Organizational Effects Hormonal Activational Effects Sex Chromosome Effects Three classes of proximate factors causing sex differences in phenotype

9 Primary sex determining genes are those that are differentially represented in male and female zygotes Arnold, Trends in Genetics 2012

10 How to vary sex chromosome complement (XX vs. XY) to observe differential effects without confounding hormonal differences?

11 Four Core Genotypes (FCG) Mice Paul Burgoyne and Robin Lovell-Badge Make gonadal determination independent of sex chromosome complement

12 Y-linked Sry is testis-determining Sry Y A3 A3 A2 A2 X A1 A1 Autosomes

13 Sry moved to an autosome Sry Y - A3 A3 A2 A2 X A1 A1 Chr3 becomes male determinings

14 Four Core Genotypes Model XY - Sry father x XX mother MICE genome gonads offspring: XX XY - XXSry XXF XYF XXM XY - Sry XYM

15 Four core genotypes Sex chromosome complement Gonadal type

16 Test phenotype in GDX mice (no activational effects) This is an organizational effect of gonadal hormones XX XY gonadal male gonadal female Main effect of gonadal sex

17 Test phenotype in GDX mice (no activational effects) This is an effect of sex chromosome complement XX XY gonadal male gonadal female Main effect of XX vs. XY

18 Case I : Sex chromosome and hormonal effects on adiposity and metabolism Xuqi Chen Karen Reue UCLA Human Genetics Jenny Link

19 Interaction of sex hormones and sex chromosomes chow (low fat diet)

20 Compensation! Sex chromosome effect and hormonal effects reduce each other. Body Weight XX>XY M>F

21 Large sex chromosome effect on fat mass XX >> XY

22 Mice with two X chromosomes are heavier and fatter than mice with one X chromosome

23 High fat diet Dramatic accumulation of liver tricylcerides HDL cholesterol XX>XY

24 Summary adiposity FCG mice Number of X chromosomes has dramatic effects after GDX on adiposity, weight gain XX eat more than XY during day Sex chromosome effect exacerbated by high fat diet Dysregulation of metabolism Large accumulation of triglycerides in liver Tremendous experimental control of individual sex-biasing factors to dissect roles of each

25 Case 2 Cardiac ischemia/reperfusion injury: One X chromosome is better than two. Jingyuan Li, Maureen Ruiz-Sundstrom, Yuichiro Itoh, Xuqi Chen, Arthur P. Arnold Mansoureh Eghbali UCLA Mansoureh Eghbali

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27 Langendorff Perfused hearts Stabilization Ischemia Reperfusion 30 min 60 min Infarct size Hemodynamic Stabilization Ischemia Reperfusion 30 min 10 min Calcium retention capacity

28 Gonadectomized XX mice have lower cardiac functional recovery after ischemia reperfusion injury compared to XY mice XXF XXM XYF XYM

29 Functional recovery of XX mice significantly lower than XY mice left ventricular developed pressure rate pressure product (RPP = HR LVDP) C. maximum rate of LV pressure rise D. Max rate LV pressure decline (-dp/dtmin)

30 Infarct size XX > XY A. Four slices of the same heart after TTC staining. White area represents the infarct zone, red shows the viable area. B. The area of necrosis as the percentage of total ventricular area, *P<0. 05(n=6-7). MXY

31 The sex chrom effect is an X chrom effect One X is better than two (XY* model)

32 Heart: Genes escaping X inactivation are expressed higher in XX than XY

33 Four points 1. Using Four Core Genotypes and XY* mouse models, we compare mice with the same gonads but with different sex chromosomes. 2. Sex chromosome complement contributes to sex differences (XX = XY). / 3. The number of X chromosomes contributes to sex differences: obesity, cardiac ischemic / reperfusion, multiple sclerosis, neural tube closure defect, Alzheimers models. 4. Sex biasing mechanisms sometimes counteract each other (compensation).

34 Arnold Lab UCLA Yuichiro Itoh Xuqi Chen Shayna Williams-Burris Mariam Barseghyan Kathy Kampf Rebecca McClusky Maureen Ruiz-Sundstrom Ryan Mackie Haley Hrncir

35 UCLA Karen Reue, Jenny Link Jake Lusis Mansoureh Eghbali Jingyuan Li, Soban Umar Eric Vilain Rhonda Voskuhl Yvette Taché Stephanie White Georgia State Univ Geert De Vries Nancy Forger Univ Virginia Emilie Rissman NIMR, London Paul Burgoyne Robin Lovell-Badge

36 UCLA Laboratory of Neuroendocrinology Art Arnold Marie-Françoise Chesselet Chris Colwell Mansoureh Eghbali Jake Lusis Allan Mackenzie-Graham Paul Micevych Barney Schlinger Eric Vilain Rhonda Voskuhl Nancy Wayne Stephanie White

37 Support: thank you! NIDDK, NICHD, NINDS, ORWH, NHLBI, NIMH, NIDCD Isis Fund, Society for Women s Health Research UCLA Iris Cantor Center, CURE, Center for Neurobiology of Stress, Parkinson s Center

38 X Y