Genetic  Disorders  And  Sex-­‐linked  Traits  

Chromosomal  Abnormalities  • Aneuploidy:  having  an  extra  or  missing  chromosome–fairly  common  in  gametes.    Errors  in  meiosis  causes  chromosomes  to  not  separate  equally  into  the  gametes.  

Aneuploidy  • Frequency  of  Aneuploidy:  

• In  males:  constant,  1-­‐2%  of  sperm  have  an  extra  or  missing  chromosome.  

   

• In  females:  rate  increases  with  age.      

 

• Illustrated  by  the  frequency  of  Down  syndrome  births  at  different  ages  of  mother.  

 

Aneuploidy    

• Except  for  the  X  and  Y,  humans  don’t  survive  with  only  1  copy  of  any  chromosome.      

 

• Also,  3  copies  is  lethal  in  most  cases.    Aneuploidy  is  a  major  cause  of  spontaneous  aborKon  in  early  pregnancy.  

 

• Down  Syndrome  is  the  most  common  human  aneuploidy.    It  is  also  called  trisomy-­‐21,  meaning  3  copies  of  chromosome  number  21.      

Examples  of  Aneuploidy  1.  Down  Syndrome  (type  of  Trisomy)  

• a  geneKc  condiKon  in  which  the  individual  has  3  copies  of  the  21st  chromosome.    

Down  Syndrome  

Down  Syndrome  • Phenotype:  small  broad  nose,  upward  slanKng  eyes  with  small  folds  in  corners,  some  cardiac  deformiKes,  moderate  to  severe  learning  disabiliKes  

• Occurs  about  1  in  1000  births.  

2.  Turner  Syndrome  • Missing  or  incomplete  X  chromosome  (XO)    

Turner  Syndrome  • Phenotype  

• Develop  physically  as  female    •  Shorter  in  stature  (missing  SHOX  gene  responsible  for  long  bone  growth)  

• Ovaries  don’t  develop  properly  (Sterile,  delayed  puberty)  

•  Stocky  build,  short  webbed  neck,  low  hairline  •  Swelling  of  hands  and  feet,  heart  issues  • Doesn’t  affect  intelligence  

• Treatment  • Hormone  therapy  helps  most/all  symptoms  except  the  sterility.  

Turner  Syndrome  •  affects  60,000  females  in  US  

•  Seen  in  1  of  every  2000  to  2500  girls  

 

•  about  800  new  cases  diagnosed  each  year.  

3.  Klinefelter  Syndrome  (XXY)  

Klinefelter  Syndrome  XXY  • The  Y  chromosome  makes  physically  male  

 

• Symptoms  (subtle  and  highly  varied)  • Typically  testes  not  fully  developed  (less  testosterone  and  inferKle)  

• May  be  taller  than  average,  proporKonally  longer  arms  and  legs,  less  muscle  development  

•  less  body  hair,  slight  breast  development,  wider  hips,  sterile,  can  have  some  learning  disabiliKes  

 

• OZen  not  diagnosed,  or  diagnosed  accidentally      

• Symptoms  helped  by  testosterone  treatment.  

Klinefelter  Syndrome  

• XXY  is  one  of  the  most  common  geneKc  condiKons,  affecKng  about  1  in  660  geneKc  males.  

Other  Aneuploidy  Examples  4.  Triplo-­‐X:    • 3  X’s  (female)  • Many  undiagnosed  because  have  no  symptoms.      

• Some  have  slight  social  and  developmental  problems,  especially  language-­‐related.      

• Occasional  ferKlity  problems,  but  many  have  normal  ferKlity.      

5.  XYY:  • Male    • Many  never  diagnosed  due  to  a  lack  of  symptoms  

• Tend  to  be  taller,  more  physically  acKve,  slight  mental  disabiliKes,  prone  to  acne.    

Hermaphrodites  ?!?  

• Hermaphrodite:  An  individual  that  has  all  female  reproducKve  parts,  and  all  male  reproducKve  parts    • No  such  thing  in  Humans  

XY  female  (2  ways  it  can  happen)  •  1.  SRY  gene  inacJvated  by  mutaJon:  testes  don’t  develop  and  the  embryo  develops  as  normal  female.  

 

•   2.  “Androgen  insensiJvity”:  person  is  XY  with  a  funcKonal  SRY  gene,  but  cells  lack  testosterone  receptor  protein,  so  the  cells  don’t  ever  get  the  message  that  the  testosterone  is  sending.      •  Testes  develop  in  the  abdominal  cavity,  and  no  ovaries,  fallopian  tubes,  or  uterus  develop.    

•   At  puberty,  the  internal  testes  secrete  testosterone,  which  gets  converted  into  estrogen  and  the  body  develops  as  a  normal  (but  sterile)  adult  female.    

XY  women  show  some  “male-­‐like”  features  that  make  them  good  models  • Phenotype:

•  Look  like  women  • Do  not  have  uterus,  don’t  have  periods  

• Some  have  testes  instead  of  ovaries  

• Taller  than  most  women  • Chiseled  Jaw  • Good  Muscle  definiKon  • Don’t  have  as  much  body  fat  

Hermaphrodites  •  In  some  cases,  androgen  insensiKvity  is  only  parKal:  the  cells  respond  a  liale  bit  to  testosterone  produced  by  the  testes.    The  embryo  develops  with  ambiguous  genitalia,  neither  completely  male  not  completely  female.      

• Another  condiKon,  congenital  adrenal  dysplasia,  causes  the  adrenal  glands  to  produce  an  abnormally  large  amount  of  testosterone  in  a  female  embryo,    This  can  also  cause  development  of  ambiguous  genitalia.  

• Another  rare  condiKon:  a  chimera  occurs  when  two  separate  embryos  fuse  together.    This  can  result  in  a  person  with  some  XX  cells  and  some  XY  cells.  This  condiKon  is  extremely  rare:  

Chromosome  Structure  Abnormalities    DuplicaJon:  an  extra  copy  of  a  region  of  chromosome  

 

DeleJon:missing  a  region  of  chromosome    

Inversion:  part  of  the  chromosome  is  inserted  backwards  

 

TranslocaJon:  two  different  chromosomes  switch  pieces    

Chromosomal  Deletion  • Cri-­‐du-­‐Chat  Syndrome  “cry  of  the  cat”  

• Caused  by  deleJon  on  the  short  arm  of  Chromosome  5  

• MulKple  genes  missing    

Cri-­‐du-­‐chat  syndrome  Symptoms:  • Small  at  birth,  larynx  doesn’t  develop  correctly  (cat-­‐like  cry),  small  head  

• Can  have  heart  defects,  problems  with  hearing  and  seeing,  poor  muscle  tone  

• Possible  HyperacKvity  or  aggression  and  severe  intellectual  disability  

Causes  of  Chromosomal  Abnormalities  • DeleKons  during  the  formaKon  of  an  egg  or  sperm,  are  caused  by  unequal  recombinaKon  during  meiosis.    

• RecombinaKon  normally  occurs  between  pairs  of  chromosomes  while  they  are  lined  up  at  the  metaphase  plate.    

• If  the  pairs  of  chromosomes  don't  line  up  correctly,  or  if  the  chromosome  breaks  aren't  repaired  properly,  the  chromosomes  can  gain  or  lose  pieces.  

Twins  • 2%  of  births  • MonozygoJc  (IdenJcal)  30%  of  twins  A  single  zygote  splits  into  2  between  1  to  9  days  aZer  the  zygote  forms.  The  twins  share  the  same  genome      

 

Dizygotic  (Fraternal)  70%  of  twins    • Two  separate  eggs  are  ferKlized  with  two  separate  sperm.    Two  totally  independent  zygotes  are  created.  

• The  twins  have  different  genomes    

 Conjoined  twins  –  very  rare  (1  in  200,000)    •  IdenKcal  twins  who  fail  to  completely  separate  aZer  the  

13th  day  aZer  ferKlizaKon.    • May  be  due  to  the  fusion,  or  incomplete  separaKon  of  zygotes.    

• May  be  two  fully  formed  individuals  connected  at  various  locaKons,  or  rarely,  parasiKc  twins,  where  one  is  much  smaller  and  less  formed,  or  even  completely  contained.  

Sex Linked Traits • Traits  that  occur  on  the  X  or  Y  chromosome  

• X-­‐linked  traits  are  traits  found  on  the  X  Chromosome    

• Since  males  only  have  one  X,  all  genes  on  it,  whether  dominant  or  recessive,  are  expressed.  

 

• A  mutant  gene  on  an  X  chromosome  in  a  female  is  usually  covered  up  by  the  normal  allele  on  the  other  X.    Most  mutaKons  are  recessive.  So,  most  people  with  sex-­‐linked  geneJc  condiJons  are  male.  

Why  can  females  have  2  copies  of  the  X  chromosome,  when  an  extra  copy  of  most  chromosomes  is  deadly  (like  having  3  of  any  other  chromosome?  

• In  each  cell  one  of  the  X  chromosomes  ‘turns  off’.  

• This  turned  off  chromosome  is  known  as  a  Barr  body.  

• The  effect  of  Barr  bodies  can  be  seen  in  Calico  colored  cats.  

Example:  Calico  Colored  cats.  A  calico  cat  has  patches  of    orange  and  patches  of  black    

XO  =  orange        XB  =  black    

Males:    XOY  =  orange    /    XBY  =  black  Females:  XOXO  =  orange  /  XBXB  =  black    /    XBXO  =  calico    

Because  individual  cells  determine  which  X  chromosome  to  deacKvate,  the  patches  of  color  arise  

Colorblindness  • We  have  3  color  receptors  in  the  reKnas  of  our  eyes.    They  respond  best  to  red,  green,  and  blue  light.  

 

• Each  receptor  is  made  by  a  gene.    The  blue  receptor  is  on  an  autosome  (chrom  7),  while  the  red  and  green  receptors  are  on  the  X  chromosome  (sex-­‐linked).  

Colorblindness    

• Most  colorblind  people  are  males,  who  have  mutated,  inacKve  versions  of  either  the  red  or  the  green  (someKmes  both)  color  receptors.      

 

• Most  females  with  a  mutant  receptor  gene  are  heterozygous:  the  normal  version  of  the  receptor  genes  gives  them  normal  color  vision.  

How to write a Alleles for Sex Linked Traits

• Women: • Normal: XBXB • Carrier: XBXb • Colorblind: XbXb

• Men: • Normal: XBY • Colorblind: XbY

Colorblind Test!

• You  will  be  given  a  colorblind  test.    • You  will  see  circles  with  many  colors  of  dots  

• The  dot  paaern  makes  up  a  number  • What  number  do  you  see?  

With Color Vision:

Color Blind Test

What number do you see?

Color Blind Test

What number do you see?

This what you would see if you were totally color blind

What  number  do  you  see?  

Color Blind Test

What number do you see?

Color Blind Test

What number do you see?

Color Blind Test

What number do you see?

Color Blind Test

What number do you see?

Everyone should see this one: •  Circle, Star, Square

• Yellow Square (Red/Green CB and Normal) • Brown circle (only Normal Vision people)

• Yellow circle (Red/Green CB and Normal) • Brown Square (only Normal Vision people)

Which do you see?

•  Normal Vision should see Boat

With color vision you see this: But if you were red-green colorblind….

You would see the #:

5

What word do you see?

Says No

Blue Color Blind

If you can't make out the '6', '0' or '4' in the 3 circles of this Ishihara color chart respectively, chances are, you have protanopia, deuteranopia, or tritanopia.

NO Red is mixed up with blue or green NO Blue or Yellow

What do the colorblind see?

NORMAL PROTAN:

Red Blind DEUTERAN: Green Blind

TRITAN: Blue Blind

RED

YELLOW

GREEN

CYAN

BLUE

MAGENTA

Types of Colorblindness

http://www.visitliverpool.jp/nature/images/knowsley-wildflower.jpg

Types of Colorblindness

Normal No color vision

Protanopia: no red Deuteranopia: no green Tritanopia: no blue

Practice  Problem  1.  A  colorblind  man  marries  a  female  who  is  a  carrier  for  colorblindness.  What  is  the  probability  that  they  will  have  a  child  who  is  colorblind?      

2.  A  male  who  can  see  in  color  marries  a  female  who  is  a  carrier  for  colorblindness.  What  are  the  possible  phenotypes  of  their  children?  

Hemophilia  • blood  does  not  clot  when  exposed  to  air    

• can  easily  bleed  to  death  from  very  minor  wounds.      

 

• treated  by  injecKng  the  proper  clonng  proteins,  isolated  from  the  blood  of  normal  people.  (Now  75%  use  geneKc  engineering)  

 

• 1  in  10,  000  males  • 1  in  100,000,000  females  

Common  amongst  royalty  in  Europe    

Queen  Victoria  =  Carrier  

Practice  Problems  3.  A  woman  with  hemophilia  marries  a  man  who  does  not  have  hemophilia.  What  are  the  possible  phenotypes  of  their  children?    4.  A  woman  without  hemophilia  marries  a  man  with  hemophilia.  They  have  a  son  with  hemophilia.  Create  a  punnea  square  for  this  family.  What  are  the  probabiliKes  of  their  offspring?