Lecture 7 - Reproduction

  1. Why do numerical changes to sex chromosomes survive better than for autosomes?

    • dosage compensation mechanisms already act on X chromosome (x inactivation)

    • Y chromosome is relatively gene poor

      • extra copies are not hugely impactful

  2. What is X-chromosome inactivation?

    • epigenetic silencing most of genes on all but one X chromosome

  3. Is it possible to have a mosaic 45,X/46,XY embryo? Is it male or female?

    • depends on definition of sex, level of mosaicism, what cell types carry which chromosome complement and give rise to downstream physiology

  4. Is it possible to have a 46, XY female? or a 46,XX male?

    • 46 XY female - possible if SRY gene deleted on Y

    • 46 XX male - possible if one X carries SRY, or if individuals has DRY mutation and cannot respond to androgens

  5. What is an ovo-testes?

    • gonad with properties of both ovaries and testes

  1. What are some examples of chromosome abnormalities that may be associated with reduced fertility in carriers?

    • Turner syndrome (45X) - streak ovaries

    • Klinefelter Syndrome (47, XXY)- male meiosis sensitive to improper pairing

    • other autosomal aneuploidies in males → fails pachytene checkpoint

  2. Why do males with chromosome abnormalities often experience infertility while females with the same abnormality might experience pregnancy loss?

    • Pachytene checkpoint is strict, ceases meiosis

      • if pairing of homologous pairs isn’t perfect, spermatogenesis does not progress

  3. What are some mechanisms that might underlie to high aneuploidy rates in human oocytes, especially with high maternal age?

    • errors in meiosis I, then frozen until fertilization → meiosis II

      • fail to form synaptonemal complex

      • failure of sister chromatid/centromere/spindle cohesion

    • at high maternal age, poorer quality oocytes, degrade from being arrested for long

  4. What kind of genetic errors increase with age of the father? Why might these be more common than in oogenesis?

    • increase in de novo mutations with age

    • related to 1000s of rounds of mitosis during spermatogenesis

  1. Increased maternal age is associated with an increase in miscarriage and infertility. Why? (i.e. what specific type of genetic errors are increased?)

    • aneupliod in oocytes

    • decline in follicular pool as proportion of poor-quality oocytes increases

    • higher recombination rates, meiosis more error prone

    • genetics, relative body comp, autoimmune diseases, short and long term stress

  2. Increased paternal age is associated with what types of genetic changes?

    • increases in de novo mutation risk - number of cell division before gamete is achieved

    • sperm counts reduce slightly

  3. In what ways can assisted reproductive technologies overcome issues around infertility?

    • IVF - harvest woman’s eggs, fertilization, grow embryos 3-5 days, then implant back into mother’s uterus

    • ICSI (intracytoplasmic sperm injection) - single sperm inserted into egg individually

  4. Meiosis

    1. When does meiosis occur (initiated and completed) in oogenesis?

      • Meiosis I - initiated embryonically, arrested until ovulation

      • Meiosis II occurs after fertilization

    2. When does meiosis occur (initiated and completed) in spermatogenesis?

      • Meiosis I and II occur after puberty in males

    3. At what point in development does recombination take place during oogenesis? Keeping this in mind, how might altered recombination relate to age-related aneuploidy?

      • Recombination - during Meiosis I (prophase)

      • increase in premature separation of sister chromatids with maternal age

        • meiosis I defects are most common cause of aneuploidy

  5. List four differences between oogenesis and spermatogenesis. How might these help explain the higher incidence of aneuploidy in oocytes vs spermatocytes?

    Oogenesis

    Spermatogenesis

    All eggs by 3 months

    Sperm produced continuously

    1 egg selected from 10-20

    1 selected from millions

    Meiosis II completed after fertilization

    Meiosis II completed prior to fertilization

    Higher recombination rates
    Meiosis is more error prone

    50% less recombination
    Meiotic pachytene checkpoint

You are a genetic counsellor meeting with a couple to discuss an abnormal amniotic fluid test result: A duplication on chromosome 15 was identified by CGH array. What is some information you would like to know to help inform your counselling of the couple ?

  • Age of couple, other health factors, environmental exposures, family history, chromosome complement

• You are a researcher and want to investigate the underlying genetic causes that contribute to congenital heart defects. You have acquired 100 DNA samples from such cases for genetic testing. What are some types of changes you might expect to be find amongst this cohort. What approach will you use to identify genetic mutations/variations in this study population and why?

  • What is duplicated? is it large or small? Has it been previously reported in patients or controls? Is it maternal or paternal? Is it de novo or inherited?