Lecture 5

Chromosome basics

1. 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

2. What features are not conserved, even sometimes between closely related species?

   • number and size of chromosomes

3. Does size or number of chromosomes matter to an organism generally? Why or why not?

   • not much, don’t correlate with total amount of DNA or gene content

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

• types of changes: numerical, structural (deletions, duplications, inversions, translocations), ring, marker

1. Roughly how common are chromosome abnormalities at conception?

   • 20% of conceptuses, 1/300 live births

2. Which trisomies can survive to term? Which are lethal and result in miscarriage?

   • survive: trisomy 13, 18, 21, XXX, XXY, XYY

   • lethal: most others

     • T1, T11, T19 too early to miscarriage

3. Why is autosomal monosomy rare in clinical pregnancies?

   • haploinsufficiency of many genes would cause massive phenotype

   • recessive mutations would be unmasked → no survival

4. What types of chromosome abnormalities might occur in

   1. a healthy adult - balanced rearrangements

   2. a child with developmental delay - deletions or duplications

   3. a newborn with major congenital anomalies - autosomal trisomies, deletions, duplications

   4. a first trimester miscarriage - numerical errors, ploidy errors, deletions, duplications

   5. a male experiencing infertility - aneuploidy

   6. a female experiencing infertility - aneuploidy or female > 35 years (eggs more likely to aneuploidy)

Some chromosome changes (e.g. 22q11.2 deletions) can have very variable phenotype in different individuals. What are some factors that 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 the 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 role these genes may play in normal circumstances

What is a Robertsonian translocation? Is it balanced or unbalanced? What type of chromosomes participate in Robertsonian translocations?

• translocations between two acrocentric chromosomes, balanced

• 13, 14, 15, 21, 22

Some deletions/duplications are recurrent, meaning they occur more often than chance and often enough to be recognized as a syndrome. Why might that be?

• repetitive regions in genome like to recombine → results in deletions

• eg. ABDC repetitive elements in Williams syndrome locus

What is triploidy? Why can triploidy generally survive longer in development than some individual trisomies which rarely persist past implantation? What can triploidy tell us about genomic imprinting?

• triploidy - three haploid sets of chromosomes

• imprinting - expression of a gene from only one allele (maternal or paternal, not both)

• in triploidy, extra set comes from maternal or paternal, creates imbalance of genes from that parent

  • phenotype of triploid depends on parental origin of haploid set

• digynic - extra maternal set (small placenta, growth-restricted fetus)

• diandric - extra paternal set (abnormally large placenta, steal maternal nutrients, less growth restriction)

What is mosaicism? Why does this typically lead to a less severe phenotype than non-mosaic carriers of an abnormality?

• mosaicism - presence of two or more cell lineages with different genotypes arising from single zygote in single individual

  • arises from acquisition of mutations after embryo has begun to grow, mutant and normal subset coexist

• can buffer genetic abnormalities, if mutant cell population is small enough, might not be disease phenotype

What is microdeletion syndrome? What causes some deletions to recur in the genome?

• microdeletion - recurrent phenotype caused by deletion of set of adjacent genes

  • typically <3Mb, not visible under microscope

What is a copy number variant (CNV)? Are they common or rare? If we detect on on prenatal diagnosis, what things might one investigate to help in determining the effect on fetal development?

• CNV - deletion or duplication

• Common (5-10%)

• Factors involved in fetal development

  more likely to be pathogenic	less likely to be pathogenic
  de novo	unaffected parent has same CNV
  large	small
  dosage-sensitive genes disrupted	few genes impacted
  rate	common in population, in healthy individuals
  similar CNVs association with disease in databases