X-linked inheritance Flashcards
Define X inactivation and describe its molecular basis and clinical relevance
- occurs early in development where one X remains active while others become permanently inactive
- Initial X inactivation decision is random, the effects are permanent in its somatic descendants of each cell
- Inactive X chromosomes remain highly condensed
-Clinical relevance=>skewed X inactivation causes ratio to be uneven which can lead to mild phenotypic consequences if a female is heterozygous for an X-linked mutation
Define X inactivation regarding its molecular basis
-Molecular=> additional modification with DNA methylation and histone modification
Define X inactivation regarding its clinical relevance
-Clinical relevance=>skewed X inactivation causes ratio to be uneven which can lead to mild phenotypic consequences if a female is heterozygous for an X-linked mutation
Define X linked inheritance and be able to track X linked traits in pedigrees including obligate carrier status.
predominantly, males are affected due to X hemizygosity so typical pattern is affected males through the maternal lineage where the females are generally just carriers
no father to son transmission
T/F In males that are XY, they are hemizygous for essentially all genes on the X chromosome
True
X^A, Y; X^a,Y
T/F Females can be either homozygous or heterozygous for genes on the X chomosome
true
In regards to the Y chromosome, it has a limited number of genes on the region of the chromosome that is referred to as what?
-pseudoautosomal region
What determines the male sex?
-SRY gene and male fertility
Describe the pseudoautosomal region of the Y chromosome
- short regions of homology on Xp and Yp (also Xq & Yq)
- Promotes sex chromosome pairing in prophase I of male meiosis
What is the only non-homologous chromosome pair?
XY chromosomes
Describe the number of X linked genes in females vs males
-2 copies in females vs 1 copy in males
In females, the expression of X linked genes is reduced to match what and through what mechanism?
-match male levels through X activation
T/F X inactivation can be reversed in somatic descendents
-False, it is permanent
Normal females are X chromosome mosaics. What does this mean in regards to their cells?
-Express the paternally derived X in half their cells and the maternally derived X in the other half
What gene is a regulator of X inactivation?
-XIST gene (X-inactivation specific transcript)
Describe the XIST gene
- produces a non-coding RNA that coats and marks the inactive chromosome
- expressed ONLY from the INACTIVE X chromosome
- mature RNA product “coats” the chromosome, “marking” it as inactive
How does the inactivated X chromosome maintain the inactive state?
-additional modification with DNA methylation and histone modification
Describe the complexity of the X inactivation in regard to regulators of the XIST gene
-complex with upstream and downstream regulators of XIST gene to achieve both initiation and maintenance of inactivation
Does the X inactivation occur in an even pattern on the chromosome?
- *-No, it is uneven along the length of the X chromosome with some genes escaping X inactivation altogether which is bi-allelic expression
- 15-20% of X linked genes are NOT inactivated but mostly on Xp**
Where do the genes generally escape the inactivation?
pseudoautosomal region
What process achieves the dosage compensation?
-epigenetic process
What is the only time when the X inactivation can be reversed?
-female germline just prior to meiosis
Recognize a punnett square for females regarding X linked recessive inheritance
X2 is a mutation
Recognize a punnett square for males regarding X linked recessive inheritance
Regarding X linked recessive inheritance, describe the relationship to the offspring to sons and daughters if the female is the carrier
- half their sons will be affected
- Half daughters will be carriers
Regarding X linked recessive inheritance, describe the relationship to the offspring to sons and daughters if the male is affected
- All daughters will be obligate carriers if able to reproduce
- No disease risk to sons
What are 4 principles of X-linked inheritance that will inform risk to potential parents toward their offspring?
family history evaluates carrier risk and recurrence risk
multiple affected family members are consistent with a familial mutation
single affected family member (new mutation or inherited mutation)
Affected females are observed rarely
How can you determine if a woman is an obligate carrier of an X linked recessive disease?
woman with 2 or more affected sons
woman with an affected brother and affected son
Why are affected females rarely observed?
-mildly affected heterozygote due to skewed X inactivation but could only be seen in a daughter of an affected male and female carrier
Why can X-linked inheritance patterns whether dominant or recessive be ambiguous?
X inactivation, reduced viability and variable expression
What is the primary mode of transmission of X-linked traits?
- primarily affect males due to hemizygous but done through carrier females
- cannot occur through male-to-male transmission
