1 / 23

Part 4

Part 4. The Inheritance of Single-Gene Differences. (2) Human pedigree analysis and organelle inheritance. Chapter 5 in Griffiths et al. Pedigrees analysis. Analysis of inheritance in human families Typically small number of offspring -> Mendelian ratios rarely observed

debra
Download Presentation

Part 4

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Part 4 The Inheritance of Single-Gene Differences (2) Human pedigree analysis and organelle inheritance Chapter 5 in Griffiths et al.

  2. Pedigrees analysis • Analysis of inheritance in human families • Typically small number of offspring • -> Mendelian ratios rarely observed • Allow inferences concerning genotypes and predictions concerning phenotypes of offspring (genetic counseling)

  3. Most common signs and symbols used in pedigree analysis

  4. Categories of inheritance • Autosomal recessive • e.g., PKU, Tay-Sachs, albinism • Autosomal dominant • e.g., Huntington’s Disease • X-linked recessive • e.g., color-blindness, hemophilia • X-linked dominant • e.g., hypophosphatemia • Y-linked • Organelle

  5. P/p P/p pp PP or Pp PP or Pp pp PP or Pp Pedigree analysis: case 1 • Two children, one of each sex, show the trait but trait was not shown in the parents • Conclusions: • must be autosomalrecessive trait (example: PKU) • parents must be heterozygous (Pp) • 2/3 chance for each unafflicted child to be heterozygous (Pp) • 1/3 chance for each unafflicted child to be homozygous (PP)

  6. Autosomal recessive inheritance in pedigrees An autosomal recessive disorder is revealed by the appearance of the phenotype in both male and female progeny of unaffected individuals, who may be inferred to be heterozygous carriers

  7. Pedigrees: Case 2 A/a a/a A/a a/a a/a a/a A/a a/a a/a A/a A/a a/a a/a a/a a/a A/a a/a A/a a/a

  8. Autosomal dominant disorders Autosomal dominant (AD) disorders are those in which both heterozygotes and homozygous dominant individuals show the abnormal phenotype. One copy of the mutant gene is sufficient for expression of the abnormal phenotype = haplo-insufficiency (Note: In fact, in some AD diseases the homozygous genotype is incompatible with life)

  9. Characteristics of pedigrees for AD disorders: • - Every individual developing the disease must have an affected parent (except in cases of de novo mutations) • Males and females are equally likely to inherit the allele and be affected (autosomal disorder) • Recurrence risk (the probability that a genetic disorder that is present in a patient will recur in another member of the family) for each child of an affected parent is 1⁄2. If one parent is a heterozygote for a particular gene, their offspring will either inherit the gene or they will not, with each outcome equally likely. • Normal siblings of affected individuals cannot pass the trait on to their offspring. If an affected individual’s siblings are not affected, they do not carry the mutation and cannot pass it on to their own offspring (thus a dominant mutant allele should be lost rapidly from the population if it affects greatly the fitness of the carrier).

  10. Typical pedigree for AD disorder A/a a/a A/a a/a a/a a/a A/a a/a a/a A/a A/a a/a a/a a/a a/a A/a a/a A/a a/a

  11. Huntington’s disease: an example of AD disorder - Half the people in the Venezuelan village of Barranquitas are affected - A large-scale pedigree analysis was conducted including 10,000 people - Example for one particular family:

  12. Huntington’s disease: an example of AD disorder • Neurological disorder causing convulsions, paralysis, loss of memory and eventually death • Affected people do not show symptoms until their 30s to 50s (so they may not know that they are affected before they have children) • Caused by programmed death of brain cells • Exact reasons why brain cells die are unknown but HD gene has been identified on Chr4. He encodes a protein of unknown function (huntingtin). • Disease caused by extension of CAG triplet within coding sequence of HD gene, resulting in a protein with a longer stretch of glutamin residues • It is the presence of this abnormal form, and not the absence of the normal form, that causes harm in HD. This explains why the disease is dominant and why two copies of the defective gene do not cause a more serious case than inheritance from only one parent.

  13. XAY XAXa XaY XAXa or XAXA? XAY XAXa or XAXA ? XAY Pedigrees: Case 3 • If allele associated with trait is very rare, this pedigree is most consistent with X-linked recessive inheritance • A single affected female would indicate autosomal (because for X-linked trait, homozygous females can only result from parents both carrying the recessive allele so affected female are very, very rare)

  14. Pedigrees: Case 3 XAY XAXa Must be XAXa XaY XAY XAXa or XAXA XAY XaY XaY XAY XAY XAXa or XAXA XaY

  15. X-linked recessive disorders are characterized by the following pedigree pattern: (1) Many more males than females develop the disease (ie. show the phenotype) (2) None of the offspring of an affected male are affected, but all of its daughters must be heterozygous carriers (half the sons born to these carrier daughters are affected)

  16. Pedigree of an X-linked recessive disorder Father affected Son non affected Daugther carrier 1/2 grandsons affected

  17. Hemophilia: an example of X-linked autosomal recessive disorder

  18. Only males develop the disease! Partial pedigree analysis of hemophilia in royal families of Europe

  19. Spontaneous mutation gave rise to defective allele of Factor VIII gene (XfXF) XfY XfXF XfXF XfXF XfXF XfXF XfXF XfY XfY XfY XfY XfY XfY XfY XfY XfY Partial pedigree analysis of hemophilia in royal families of Europe Is it possible that the present British family still harbors the recessive allele?

  20. Spontaneous mutation gave rise to defective allele of Factor VIII gene (XfXF) XfY XfXF XfXF XfXF XfXF XfXF XfXF XfY XfY XfY XfY XfY XfY XfY XfY XfY Partial pedigree analysis of hemophilia in royal families of Europe XfXF ? XfXF\? Must be XFY, even if mother was XfXF (otherwise he would be sick) so Xf allele was lost in this branch of the family

  21. X-linked dominant disorders are characterized by the following pedigree pattern: (1) Affected males pass the condition on to all their daughters but none of their sons (unlike dominant autosomal disorders where daugthers and sons have an equal probability to inherit the disease) (2) Affected females are mostly heterozygotes. When married to unaffected males, they pass the condition on to 1/2 of their sons and 1/2 of their daughters (same pattern than for autosomal dominant disorder) Note: X-linked dominant disorder are rare traits in human (ex: hypophosphatemia: low levels of inorganic phosphate in the blood.) Diagnose is complicated by the process of X inactivation in females.

  22. Case 4: X-linked dominant disorders

  23. Remember that the probability that two independent events will both occur is the product of their individual probabilities.

More Related