Lecture 5

What features of chromosomes are conserved between all organisms?

Contain and package DNA, telomere caps, replicate by forming 2 sister chromatids joined by a centromere.

What features are not conserved between organisms?

Number and size of chromosomes.

Does the size or number of chromosomes matter to an organism generally?

Not much; they do not correlate with total amount of DNA or gene content.

What kinds of numerical and structural chromosome changes arise in humans?

Numerical and structural changes include deletions, duplications, inversions, translocations, ring chromosomes, and markers.

How common are chromosome abnormalities at conception?

20% of conceptuses and 1 in 300 live births.

Which trisomies can survive to term, and which are lethal?

Survive: trisomy 13, 18, 21, XXX, XXY, XYY; lethal: most others (eg. T1, T11, T19)

Why is autosomal monosomy rare in clinical pregnancies?

Haploinsufficiency of many genes would cause massive phenotype; recessive mutations would be unmasked leading to no survival.

What kinds of chromosome abnormalities might occur in a first trimester miscarriage?

Numerical errors, ploidy errors, deletions, duplications.

What kinds of chromosome abnormalities might occur in a healthy adult

Balanced rearrangmeent

What kinds of chromosome abnormalities might occur in a child with developmental delay

deletions or duplications

What kinds of chromosome abnormalities might occur in a newborn with major congenital anomalies

Autosomal trisomies, deletions and duplications

What kinds of chromosome abnormalities might occur in a male experiencing infertility

Aneuploidy

What kinds of chromosome abnormalities might occur in a female experiencing infertility

Aneuploidy or female is greater than 35 years

What factors might cause phenotypic variability amongst carriers

Different deletion size, genetic background
Environmental factors, epigenetic effects
Unmasking autosomal recessive mutations on remaining chromosome
Parent of origin effects
Genetic variability of intact chromosome

How can investigating genetic basis of phenotypic features associated with chromosome abnormalities help us understand health issues in chromosomal typical individuals

Learn about which genes/genomic regions are relevant in certain phenotypes or dev pathways

Understand effect of genes impacted in these cases and what roles these genes may play in normal circumstances

What is a Robertsonian translocation?

Translocation between two acrocentric chromosomes; it is balanced.

Which chromosomes are acrocentric?

13, 14, 15, 21, 22

What is triploidy, and how does it relate to genomic imprinting?

Triploidy is three haploid sets of chromosomes; the phenotype depends on parental origin of the extra set.

Imprinting is the expression of a gene from only one allele (maternal or paternal)

Extra set of chromosomes creates imbalance of genes from that parent
- phenotype depends on parental origin of extra haploid set

Digynic

Extra maternal set; small placenta, growth-restricted fetus

Diandric

Extra paternal set; abnormally large placenta, steal maternal nutrients, less growth restriction

Why are some deletions/duplications recurrent enough to be recognized as a syndrome

they often occur on repetitive regions which like to recombine → results in deletions

eg. ABDC repetitive elements in Williams syndrome locus

What is mosaicism

presence of two or more cell lineages with different genotypes arising from single zygote in single individual (mutant and normal subsets exist)
Arises from acquisition of mutations after embryo has begun to grow

Why does mosaicism typically lead to a less severe phenotype?

Can buffer genetic abnormalities, if mutant subset population is small, might not be enough to cause disease phenotype

What is microdeletion syndrome?

Recurrent phenotype caused by deletion of set of adjacent genes
Recur because of homologous crossing over in same regions

What is a copy number variant and are they common or rare?

CNV - structural variation where number of copies of a DNA segment varies between people (deletion or duplication)
They are common

What factors indicate pathogenicity in CNVs

De novo, large, dosage-sensitive genes disrupted, rare, similar CNVs associated with disease in databases

What factors might indicate a CNV is not pathogenic

Unaffected parent has same CNV, small, few genes impacted, common in population in healthy individuals