Sex-Influenced Inheritance

Question 1

What is pseudo‐autosomal Inheritance?

Answer 1

• Genes near the telomers of X & Y are inherited INDEPENDENTLY of sex
  
  • behave as if on autosome, no sex-specific inheritance
  • PAR1 & PAR2

Why does this happen?

• ALWAY crossover on each arm of the sex chromosomes
• 100% recombination = independent assortment

NOTE:

• Chiasmata = required to stabilize chromosome pairs on the Metaphase plate during Meiosis 1

Example:

• SHOX locus
  
  • causes dyschondrosteosis = disorder of leg bone growth when mutated

Question 2

What is the role of the SRY Gene?

Answer 2

SRY Gene

• Basics:
  
  • encodes transcriptor factor protein
    
    • controls expression of OTHER genes
  • initiates the program for male development
• Fun facts:
  
  • X chromosome w/ SRY gene = phenotypically male
  • Y chromosome w/out SRY = phenotypically female

Question 3

What are Sex‐limited Traits?

Answer 3

• Traits that affect a structure/function normally occuring only in ONE gender
  
  • may be autosomal or X-linked
  • present in the genomes of both males & females
    
    • unexpressed in one or the other
• Examples:
  
  • Beard growth
  • Milk production
  • Pregnancy phenotypes
  • Sperm production levels
• Disorder:
  
  • Male-limited precocious puberty
    
    • mutation of LCGR locus
    • autosomal gene = encoding leuteinizing hormone receptor

Question 4

Sex‐influenced Traits

Answer 4

• Basics:
  
  • Traits that are expressed even as a heterozygote, and are influenced by gender
  • ​Allele appears dominant in one gender, and recessive in the other
    
    • responsible gene may NOT be on the X or Y chromosome

Example:

• Pattern baldness = sex-influenced trait
  
  • m/m = both men & women bald
  • m/+ = bald men & normal woman
  • +/+ = both normal

Question 5

What is Genomic Imprinting?

Answer 5

Basics:

• silencing of expression of clusters of genes on a particular chromosome
  
  • inherited from parents
• Epigenetic event:
  
  • reversible DNA methylation
    
    • alters expression capacity of a DNA domain w/o altering underlying DNA

Maintanence:

• imprints = maintained in MITOTIC divsions
  
  • LOST in meiosis
    
    • ​females = only keeps moms imprinting in oocyte
    • males = only keeps dads imprinting in oocyte

Importance:

• Takes 2 opposite sex parents = make a healthy embryo
  
  • genes from female parent = direct different activities than male parent
  • may explain incomplete penetrance in some instances

Question 6

Imprinting & Human Disease

Answer 6

• Prader-Willi Syndrome
  
  • inherited mutation PATERNALLY
    
    • MATERNAL allele = naturally silenced
  • SNRPN = NOT expressed
  • E6AP = expressed
    
    • obese/intellectual disability/hyperphagia
• Angelman Syndrome
  
  • inherited mutation MATERNALLY
    
    • ​PATERNAL allele = naturally silenced
  • E6AP = not expressed
  • SNRPN = expressed
    
    • ​slender/freq laughter/seizures/developmental delay

Distinct syndroms caused by:

• Deletion of the SAME chromosomal region: 15q11-13
• Uniparental disomy = both copies came from same parent
  
  • may originate as trisome + chromosome loss

Notes:

1. SNRPN = small nuclear ribonuclear protein –> mRNA processing
2. E6AP = analough to E3A in Ub ligase

Question 7

What is Repeat Expansion and Genetic Anticipation?

Answer 7

• All trinucleotide repeat (TNR) expansion disorders originate in unstable trinucleotide repeat sequences.
  
  • ​Ex: glutamine (CAG), aspartate (GAC), alanine (GCG) –> poly = toxic
    
    • ​instability = expressed in single generation
      
      • parents healthy while offspring = risk of disease
    • possibly due to: DNA replication slippage, repair, or recomination
• Repeat number correlates with both the severity of the disease and the age of the onset
• ​TNR displays = genetic anticipation
  
  • ​progressively earlier age of onset in subsequent generations

Disorder:

1. Myotonic dystrophy

2. Huntingdon Disease (HD)

• ​Huntingtin Protein
  
  • ​CAG repeat = poly-Glutamine sequence
    
    • Both normal + mutant proteins = expressed in Heterozygotes
    • Does not produce loss of fxn, but _alters protein produc_t

Basics of disorders:

• genetic anticipation + age of onset
• leads to = loss of function or “toxic” effect to alterations in mRNA
• “trans-dominant” = structurally abnormal –> messing up normal gene function
• Location pof repeat expansison w/in genes = differs
  
  • UTRs, protein coding regions or 3’UTR of mRNA
    
    • HD = protein-coding region
• Pathogenesis = resultant disease differs
  
  • depends on distruction from “normal”
• Parent-of-origin biases on repeat expansion rates = noted
  
  • some effects transmitted via paternal chromosome ONLY
  • some effects transmitted via maternal chromosome ONLY