I. Allelic, Genic, and Environmental Interactions A. Overview: B. Intralocular Interactions

1. I. Allelic, Genic, and Environmental Interactions A. Overview: B. Intralocular Interactions C. Interlocular Interactions D. Environmental Effects: The environment - the cellular environment as well as the environment outside the organism - can influence whether and howan allele is expressed ,and the effect it has. Typically, what we see is that a gene is only expressed under certain conditions. This is called “conditional expression”, like conditional lethality discussed earlier.

2. D. Environmental Effects: 1. TEMPERATURE - Siamese cats and Himalayan rabbits – dark feet and ears, where temps are slightly cooler. Their pigment enzymes function at cool temps. If raised at cooler temps, they are more pigmented… even looking like a genetically melanic form. When this happens in rabbits, the Himalayan genotype is expressing a phenocopy – copying the phenotype of another genotype. - Arctic fox, hares – their pigment genes function at high temps and are responsible for a change in coat color in spring and fall, and a change back to white in fall and winter. So, these genes have conditional expression.

3. D. Environmental Effects: 1. TEMPERATURE 2. TOXINS - people have genetically different sensitivities to different toxins. Certain genes are associated with higher rates of certain types of cancer, for example. However, they are not ‘deterministic’… their effects must be activated by some environmental variable. PKU = phenylketonuria… genetic inability to convert phenylalanine to tyrosine. Phenylalanine can build up and is toxic to nerve cells. Single gene recessive disorder. But if a homozygote recessive eats a diet low in phenylalanine, no negative consequences develop. So, the genetic predisposition to express the disorder is influenced by the environment. These genes haveconditional expression.

4. D. Environmental Effects: 1. TEMPERATURE 2. TOXINS 3. THE GENETIC ENVIRONMENT – “EPIGENETICS” Epigenetics is the study of the heritable changes in the expression of genes unrelated to changes in the actual DNA sequence of the genes. Heritable changes due to different patterns in gene regulation - within an organism: tissue specialization, resulting in heritable changes in a cell line through mitotic generations, creating different cell and tissue types (even though they all have the same DNA). - between organisms: regulatory differences between monozygotic twins make them phenotypically different, even though they are genetically identical.

5. D. Environmental Effects: 1. TEMPERATURE 2. TOXINS 3. THE GENETIC ENVIRONMENT – “EPIGENETICS” 1. Position Effects - the effect of a gene may be influenced by WHERE it is in the genome – and its immediate neighbors. Genes can change position due to a variety of mutations. It may be placed next to or into densely coiled ‘heterochromatin’ and be turned off. Or, it may be placed next to an ‘enhancer’ and ‘up-regulated’ (turned on more). Position effect variegation in eye pigmentation in Drosophila.

6. 1. Position Effects Can’t be transcribed – ‘off’ Can be transcribed – ‘on’

7. 1. Position Effects Human Diseases Caused by Position Effects Aniridia (malformed iris in the eye) X-linked deafness B-Thalassemia SRY sex reversal Split hand and foot malformation

8. D. Environmental Effects: 1. TEMPERATURE 2. TOXINS 3. THE GENETIC ENVIRONMENT – “EPIGENETICS” 1. Position Effects 2. Imprinting - The effect of a gene can depend on the parent it is inherited from. During gamete formation, both sexes selectively ‘imprint’ certain genes. This amounts to turning them on or off, regardless of their previous state in the organisms own body.

9. 2. Imprinting - “insulin-like growth factor 2” (igf-2) is a protein, produced in mammalian liver cells, that circulates in the blood. It stimulates cell growth and mitosis during fetal development. Mutation / inactivation causes small size at birth.

10. 2. Imprinting - “insulin-like growth factor 2” (igf-2) is a protein, produced in mammalian liver cells, that circulates in the blood. It stimulates cell growth and mitosis during fetal development. Mutation / inactivation causes small size at birth. Mutant male x normal female ss SS Normal male x mutant female SS ss Ss Ss All heterozygous, but all small All heterozygous, but all normal RECIPROCAL CROSSES YIELD DIFFERENT RESULTS – THE SEX OF THE PARENT EXPRESSING NORMAL SIZE “MATTERS” FOR THE PHENOTYPE OF THE OFFSPRING. If the gene for normal growth comes from males, it is ON, if it comes from females, it is OFF.

11. 2. Imprinting Confirmed in the F1 X F1 CROSS: Activity is not a function of the animal’s own sex, it is a function of the sex of the parent that gave the gene. This example is a bit misleading… it equates ‘imprinting’ only with the female turning the gene off. But imprinting is regulation that can also turn a gene on.

12. Small Small 2. Imprinting Confirmed in the F1 X F1 CROSS: ‘off’ in this male ‘off’ in this female The same pattern occurs when SMALL heterozygotes are mated together. ‘Imprinting’ occurs during gamete formation, with males turning ON the gene in sperm (although it was off in their own cells), and females turning OFF the gene in eggs (which was also ‘off’ in their own cells). Imprinted ‘on’

13. 2. Imprinting - why? Haig ‘Parental Conflict’ Hypothesis: - selection will favor males that increase the growth of their offspring, so they should pass on igf-2 genes that are ON. - but the female actually provides the energy for embryonic growth, and the energetic demands of maximal embryonic growth will reduce her survival and subsequent reproduction. Her most adaptive reproductive strategy is to reduce the growth of embryos to a reasonable level that doesn’t threaten her own survival. - she turns OFF her igf-2 genes that she passes to her offspring. Different selective pressures on males and females, selecting for different behaviors, different patterns of energy allocation, and different patterns of gene activation.

14. 2. Imprinting - why? Haig ‘Parental Conflict’ Hypothesis: - selection will favor males that increase the growth of their offspring, so they should pass on igf-2 genes that are ON. - but the female actually provides the energy for embryonic growth, and the energetic demands of maximal embryonic growth will reduce her survival and subsequent reproduction. Her most adaptive reproductive strategy is to reduce the growth of embryos to a reasonable level that doesn’t threaten her own survival. - she turns OFF her igf-2 genes that she passes to her offspring. A Test: The igf-2 receptor protein in cell membranes. - this receptor degrades the igf-2 protein, reducing its effect on growth. - Haig and Graham predicted this should be imprinted as well, and OFF when passed from males and ON when passed from females, based on the ‘parental conflict’ hypothesis. - when tested, it had this pattern of imprinting – supporting their hypothesis.

15. 2. Imprinting - why? - how? - methyl groups are added to cytosines in CG sequences in the promoter (“CpG islands”), interrupting the binding of the RNA polymerase, stopping transcription (turning the gene OFF).

16. 2. Imprinting - why? - how? - are they common and important? rare - ~80 have been identified in 30 years, in animals and plants.

17. 2. Imprinting - why? - how? - are they common and important? rare - ~80 have been identified in 30 years, in animals and plants. But in humans, several diseases are caused by the failure to inherit correctly imprinted genes.

18. Prader-Willi Syndrome: - hunger and weight gain - cognitive disability - reduced sex organs - decreased muscle tone

19. Prader-Willi Syndrome: - hunger and weight gain - cognitive disability - reduced sex organs - decreased muscle tone Caused by deletion in the 15q11-13 region in the father. This region is methylated (‘off’) in eggs, and should be ON in sperm. Deletion in the father results in embryos that lack one gene (from father) and have an inactive gene from mother (imprinted).

20. Angelman Syndrome: - neurological disorder - seizures - smiling and happy - microcephaly Caused by deletion of a single gene (UBE3A) in 15q11-13 region in mother. This gene is methylated in sperm, and should be ON in eggs. Deletion in the mother results in embryos that lack one gene (from mother) and have an inactive gene from father (imprinted).

21. These conditions can also occur when a zygote receives both chromosomes from one parent (we’ll see how this happens later). Heterodisomy = both homologs given from one parent Isodisomy = replicates of one homolog given from one parent MOTHER FATHER Maternal deletion Paternal Imprint (‘off’) Heterodisomy Isodisomy Isodisomy normal normal Angelman Angelman Angelman Angelman

22. D. Environmental Effects: 1. TEMPERATURE 2. TOXINS 3. THE GENETIC ENVIRONMENT - Epigenetics 1. Position Effects 2. Imprinting 3. Maternal Effects – Genotype of mother determines phenotype of offspring - by contributing her proteins to the egg, which influence early development of embryo (regardless of the embryo’s genotype for this trait).

23. 3. Maternal Effects: In Limnaea snails, left-handed(sinistral) coiling is recessive (dd) to dextral (D-). - But reciprocal crosses yield different results; F1 het’s that had sinistral mothers are sinistral, even though they have the Dd genotype, themselves.

24. 3. Maternal Effects: In Limnaea snails, left-handed(sinistral) coiling is recessive (dd) to dextral (D-). - When the Dd heterozygotes (sinistral or dextral) are self-crossed (so the “mother’ is genetically dextral (and produces dextral proteins in her eggs even though it wasn’t in her own body cells) – all the offspring (even the ¼ dd) are dextral. All dextral, even dd

25. 4. The Cellular Environment of the Egg - Maternal Effects: All dextral, even dd

26. D. Environmental Effects: 1. TEMPERATURE 2. TOXINS 3. THE GENETIC ENVIRONMENT - Epigenetics 1. Position Effects 2. Imprinting 3. Maternal Effects – Genotype of mother determines phenotype of offspring - by contributing her proteins to the egg, which influence early development of embryo (regardless of the embryo’s genotype for this trait). - through extrachromosomal inheritance – the inheritance of genes “outside” the nuclear chromosomes, rganelles like mitochondria and chloroplasts that have DNA also. These organelles are donated only in the EGG, and so are another potential source of a maternal effect.

27. - through extrachromosomal inheritance – the inheritance of genes “outside” the nuclear chromosomes, in organelles like mitochondria and chloroplasts that have DNA also. These organelles are donated only in the EGG, and so are another potential source of a maternal effect. Problem of Recognizing the effects because of HETEROPLASMY – there are hundreds of organelles in each cell, so seeing the effects of a loss-of-function mutant are difficult, and may happen only in a few cells in a tissue that happen to randomly get more mutant organelles.

28. Myoclonic epilepsy and ragged red fiber disease (MERFF) in humans - caused by mitochondrial mutations affecting aerobic respiration (decreasing ATP production). - cells with lots of these mitochondria don’t function well; this is especially debilitating in tissues with high energy demand, like neural and muscle tissue. - causes lack of muscle control, seizures, deafness, and dementia - passed maternally; children of afflicted fathers do not inherit mutant mitochondria. a) Mild proliferation of mutant mitochondria. b) high proliferation; cell full of mutant mitochondria

29. - through extrachromosomal inheritance – the inheritance of genes “outside” the nuclear chromosomes, in organelles like mitochondria and chloroplasts that have DNA also. These organelles are donated only in the EGG, and so are another potential source of a maternal effect. Problem of Recognizing the effects because of HETEROPLASMY – there are hundreds of organelles in each cell, so seeing the effects of a loss-of-function mutant are difficult, and may happen only in a few cells in a tissue that happen to randomly get more mutant organelles.

30. 3. THE GENETIC ENVIRONMENT - Epigenetics 1. Position Effects 2. Imprinting 3. Maternal Effects 4. Sex-Limited and Sex-Influenced Traits - the expression of an autosomal trait depends on the sex of the organism, probably as a consequence of the hormonal environment. Sex-Limited: only expressed on one sex, males have genes for milk production, but don’t produce milk. Sex-influenced: more frequent in one sex than another pattern baldness – Bb males bald, Bb females not

31. I. Allelic, Genic, and Environmental Interactions A. Overview: B. Intralocular Interactions C. Interlocular Interactions D. Environmental Effects E. The “Value” of an Allele 1. There are obvious cases where genes are bad – lethal alleles 2. But there are also ‘conditional lethals’ that are only lethal under certain conditions – like temperature-sensitive lethals. 3. And for most genes, the relative value of one allele over another is determined by the relative effects of those genes in a particular environment. And these relative effects may be different in different environments.

32. I. Allelic, Genic, and Environmental Interactions A. Overview: B. Intralocular Interactions C. Interlocular Interactions D. Environmental Effects E. The “Value” of an Allele Survivorship in U.S., sickle-cell anemia (incomplete dominance, one gene ‘bad’, two ‘worse’) SS Ss ss

33. I. Allelic, Genic, and Environmental Interactions A. Overview: B. Intralocular Interactions C. Interlocular Interactions D. Environmental Effects E. The “Value” of an Allele Survivorship in U.S., sickle-cell anemia Survivorship in tropical Africa (incomplete dominance, one gene ‘bad’, (one gene ‘good’, two ‘bad’) two ‘worse’) SS Ss ss SS Ss ss

34. Malaria is still a primary cause of death in tropical Africa (with AIDS). The malarial parasite can’t complete development in RBC’s with sickle cell hemoglobin… so one SC gene confers a resistance to malaria without the totally debilitating effects of sickle cell. I. Allelic, Genic, and Environmental Interactions A. Overview: B. Intralocular Interactions C. Interlocular Interactions D. Environmental Effects E. The “Value” of an Allele Survivorship in U.S., sickle-cell anemia Survivorship in tropical Africa (incomplete dominance, one gene ‘bad’, (one gene ‘good’, two ‘bad’) two ‘worse’) Survival in U. S. Survival in Tropics SS Ss ss SS Ss ss

35. As Darwin realized, selection will favor different organisms in different environments, causing populations to become genetically different over time. I. Allelic, Genic, and Environmental Interactions A. Overview: B. Intralocular Interactions C. Interlocular Interactions D. Environmental Effects E. The “Value” of an Allele Survivorship in U.S., sickle-cell anemia Survivorship in tropical Africa (incomplete dominance, one gene ‘bad’, (one gene ‘good’, two ‘bad’) two ‘worse’) SS Ss ss SS Ss ss