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Genes, Chromosomes, and Human Genetics

Genes, Chromosomes, and Human Genetics. Genetic Linkage and Recombination. The principles of linkage and recombination were determined with Drosophila Recombination frequency can be used to map chromosomes Widely separated linked genes assort independently. Chromosomes. Genes

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Genes, Chromosomes, and Human Genetics

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  1. Genes, Chromosomes, and Human Genetics

  2. Genetic Linkage and Recombination • The principles of linkage and recombination were determined with Drosophila • Recombination frequency can be used to map chromosomes • Widely separated linked genes assort independently

  3. Chromosomes • Genes • Sequences of nucleotides in DNA • Arranged linearly in chromosomes

  4. Linked Genes • Genes carried on the same chromosome • Linked during transmission from parent to offspring • Inherited like single genes • Recombination can break linkage

  5. Drosophila melanogaster • Fruit fly • Model organism for animal genetics • Compared to Mendel’s peas • Used to test linkage and recombination

  6. Gene Symbolism • Normal alleles (wild-type) • Usually most common allele • Designated by “+” symbol • Usually dominant Wild-typeMutant + = red eyes pr = purple + = normal wings vg = vestigial wings

  7. Genetic Recombination • Alleles linked on same chromosome exchange segments between homologous chromosomes • Exchanges occur while homologous chromosomes pair during prophase I of meiosis

  8. Evidence for Gene Linkage

  9. Linked genes • Genes that are close together on the same chromosome • Belong to the same linkage group

  10. Linkage and Recombination • Linkage; genes are inherited together • Crossing over produces recombination – breaks up the association of genes that are linked

  11. Notation for linkage • AABB X aabb

  12. Recombination Frequency • Amount of recombination between two genes reflects the distance between them • The greater the distance, the greater the recombination frequency • Greater chance of crossover between genes

  13. Recombination Frequency

  14. Mapping of Genes • Where is the gene is located on a chromosome? • Linkage maps – • A chromosome map; abstract based on recombinant frequencies • Physical maps – • Mapping the positions of cloned genomic fragments

  15. Linkage Maps • First genetic map • Alfred Sturtevant in the lab of Thomas Hunt Morgan • Observed that some pairs of genes do not segregate randomly according to Mendel’s principle of independent segregation • Proposed genes were located on the same chromosome • Variation in the strength of linkage determined how genes were positioned on the chromosome

  16. Chromosome Maps • Recombination frequencies used to determine relative locations on a chromosomeLinkage map for genes a, b, and c:

  17. Map: Drosophila Chromosome

  18. Predicting the outcomes of crosses with linked genes Determining proportions of the types of offspring requires knowing the RF

  19. RF = 16%

  20. Gene mapping with RFs • Genetic maps • Calculated by RFs • Measured in map units or centimorgans (cM) • RF can not exceed 50%, at 50% cannot distinguish between genes on the same or different chromosomes • Double crossovers – underestimate distance

  21. Recombination Occurs Often • Widely separated linked genes often recombine • Seem to assort independently • Detected by testing linkage to genes between them

  22. Sex-Linked Genes • In both humans and fruit flies, females are XX, males are XY • Human sex determination depends on the Y chromosome

  23. Sex-Linked Genes • Sex-linked genes were first discovered in Drosophila • Sex-linked genes in humans are inherited as they are in Drosophila • Inactivation of one X chromosome evens out gene effects in mammalian females

  24. Sex Chromosomes • Sex chromosomes determine gender • X and Y chromosomes in many species • XX: female • XY: male • Other chromosomes are called autosomes

  25. Sex Determination in Humans

  26. Human Sex Chromosomes • Human X chromosome • Large (2,350 genes) • Many X-linked genes are nonsexual traits • Human Y chromosome • Small (few genes) • Very few match genes on X chromosome • Contains SRY gene • Regulates expression of genes that trigger male development

  27. Conclusions • At least one copy of X is required for human development • Male-determining gene is on the Y; a single copy produces a male regardless of the number of X’s • Absence of Y is female • Genes affecting fertility are on the X and Y • >X’s produces physical and mental disabilities

  28. Sex determination in humans • Sex reversed individuals • XX males and XY females • Clues that there is a gene on the Y that determines maleness

  29. Proof that SRY is the male-determining gene Experiment in mice

  30. SRY gene • When mouse sry was injected into the genome of a XX zygote, the transgenic female mice developed as males (sterile)

  31. Function of SRY • DNA binding protein • transcription factor • Initiates a sex switch – • Acts on genes in the undifferentiated gonad, transforming it into a testis • Once the testis has developed testosterone is produced for male secondary sex characteristics • If no SRY, the gonad develops into an ovary

  32. Androgen Insensitivity • If the androgen receptor (AR) is deleted or null in function then testosterone can not act and no maleness results • Results from a mutation in the AR

  33. Evolution of the Y • BioInteractive's Animation Console: Y Chromosome

  34. Hey! Females have two X’s and males only have one! Females are superior?

  35. Dosage Compensation • X-inactivation • Mary Lyon Barr Body

  36. Dosage Compensation • X-inactivation • XXY males have a Barr body • XO females have none • Barr body is the inactivated X

  37. Dosage Compensation • X-inactivation • In human females an X chromosome is inactivated in each cell on about the 12th day of embryonic life

  38. Dosage Compensation • X-inactivation • X-inactivation is random in a given cell • Heterozygous females show mosaicism at the cellular level for X-linked traits

  39. How is the X chromosome inactivated?

  40. How is the X chromosome inactivated? X inactivation specific transcript (Xist) gene

  41. X-inactivation center (XIC) • Gene for XIST • Encodes an XIST RNA which is expressed solely from the inactive X-chromosome • Coats the inactive X and is involved in gene silencing • Several genes remain active (PAR and others)

  42. Calico Cats • Heterozygote female (no male calico cats)

  43. Barr Body • Tightly coiled condensed X chromosome • Attached to side of nucleus • Copied during mitosis but always remains inactive

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