non men deli an

1

NON-MENDELIAN

INHERITANCE

Chapter 7

2

NON-MENDELIAN INHERITANCE

• Mendelian inheritance patterns– Involve genes directly influencing traits– Obey Mendel’s laws

• Law of segregation

• Law of independent assortment

– Include• Dominant / recessive relationships

• Gene interactions

• Phenotype-influencing roles of sex and environment

– Most genes of eukaryotes follow a Mendelian inheritance pattern

3

NON-MENDELIAN INHERITANCE

• Many genes do not follow a Mendelian inheritance pattern– e.g., Closely linked genes do not follow Mendel’s law

of independent assortment– This chapter will discuss additional and more bizarre

non-Mendelian inheritance patterns• Maternal effect

• Epigenetic inheritance

• Extranuclear inheritance

4

MATERNAL EFFECT• Maternal effect

– Inheritance pattern for certain nuclear genes– Genotype of mother directly determines phenotype of

offspring• Genotype of father and offspring are irrelevant

– Explained by the accumulation of gene products mother provides to developing eggs

5

MATERNAL EFFECTA. E. Boycott (1920s)

• First to study an example of maternal effect

• Involved morphological features of water snail– Limnea peregra– Shell and internal organs can be either right- or left-

handed• Dextral or sinistral, respectively

• Determined by cleavage pattern of egg after fertilization

– Dextral orientation is more common and dominant

6

MATERNAL EFFECTA. E. Boycott (1920s)

• Began with two different true-breeding strains– One dextral, one sinistral

• Dextral ♀ x sinistral ♂ dextral offspring

• Reciprocal cross sinistral offspring

• Contradict a Mendelian pattern of inheritance

7

MATERNAL EFFECTA. E. Boycott (1920s); Alfred Sturtevant (1923)

• Sturtevant proposed that Boycott’s results could be explained by a maternal effect gene– Conclusions drawn from F2

and F3 generations

– Dextral (D) is dominant to sinistral (d)

– Phenotype of offspring is determined by genotype of mother

8

MATERNAL EFFECT• Oogenesis in female animals

– Oocyte is formed• Will ultimately become haploid

– Nourished by surrounding diploid maternal nurse cells

9

MATERNAL EFFECT• Oogenesis in female animals

– Oocyte is formed• Will ultimately become haploid

– Nourished by surrounding diploid maternal nurse cells

• Receives gene products from nurse cells

• Genotype of nurse cells determines gene products in oocyte

10

MATERNAL EFFECT• Maternal effect genes

– Encode RNA and proteins that play important roles in early steps of embryogenesis

• e.g., Cell division, cleavage pattern, body axis orientation

– Defective alleles tend to have dramatic phenotypic effects

11

MATERNAL EFFECT• Maternal effect genes

– Identified in Drosophila melanogaster (and other organisms)

• Profound effects on early stages of development

• Gene products important in proper development along axes– Anterio-posterior axis

– Dorso-ventral axis

• Discussed further in chapter 23

12

EPIGENETIC INHERITANCE• Epigenetic inheritance

– Modification occurs to a nuclear gene or chromosome– Occur during spermatogenesis, oogenesis, and early

stages of embryogenesis– Gene expression is altered

• May be fixed during an individual’s lifetime

– Expression is not permanently changed over multiple generations

• DNA sequence is not altered

13

EPIGENETIC INHERITANCE• Two types of epigenetic inheritance will be

discussed– Dosage compensation

• Offsets differences in the number of sex chromosomes

• One sex chromosome is altered

– Genomic imprinting• Occurs during gamete formation

• Involves a single gene or chromosome

• Governs whether offspring express maternally- or paternally-derived gene

14

DOSAGE COMPENSATION• Males and females of many species have

different numbers of certain sex chromosomes– e.g., X chromosomes– The level of expression

of many genes on sex chromosomes is similar in both sexes

15

DOSAGE COMPENSATION• Apricot eye color in Drosophila

– Conferred by an X-linked gene– Homozygous females resemble hemizygous males– Females heterozygous for the apricot allele and a

deletion have paler eye color– Two copies of the allele in a female produce a

phenotype similar to one copy in a male– The difference in gene dosage is being compensated

at the level of gene expression

16

DOSAGE COMPENSATION• Dosage compensation does not occur for all eye

color alleles in Drosophila– e.g., Eosin eye color

• Conferred by an X-linked gene

• Homozygous eosin females have darker eye color than hemizygous eosin males

– Dark eosin and light eosin

• Females heterozygous for the eosin allele and the while allele have light eosin eye color

• Two copies of the allele in a female produce a phenotype different than one copy in a male

17

DOSAGE COMPENSATION• Most X-linked genes show dosage compensation

• Some X-linked genes do not

• Reasons for the difference are not understood

18

DOSAGE COMPENSATION• Mechanisms of dosage compensation

– Mammals• One X chromosome is inactivated in females

– “X inactivation”

– Paternally derived in marsupial mammals

– Paternal or random, depending on species of placental mammal

– Drosophila melanogaster• Twofold increase in expression of genes on the X

chromosome of males

– The nematode Caenorhabditis elegans• 50% reduction in expression of X-linked genes in XX

individuals

19

DOSAGE COMPENSATION

20

DOSAGE COMPENSATION• Dosage compensation is poorly understood in

certain species– e.g., Birds and fish

21

DOSAGE COMPENSATION• Sex in birds is determined by Z and W sex

chromosomes– Males are ZZ, females are ZW– The Z chromosome is large

• Contains most sex-linked genes

– The W chromosome is a smaller microchromosome• Contains a large amount of non-coding repetitive DNA

– Dosage compensation usually occurs, but not for all genes

• Molecular mechanism is not understood– Highly compacted chromosomes are not seen in males– Perhaps genes on both Zs are downregulated– Perhaps genes on females Z are upregulated

22

DOSAGE COMPENSATIONMurray Barr and Ewart Bertram (1949)

• Identified a highly condensed structure in interphase nuclei of somatic cells of female cats– This structure was absent in male cats– “Barr body”– Later identified as a highly

condensed X chromosome

23

DOSAGE COMPENSATIONMary Lyon (1961)

• Aware of Barr and Bertram cytological evidence

• Also aware of mammalian mutations producing a variegated coat color pattern– e.g., Calico cats are heterozygous

for X-linked alleles determining coat color

• Possess randomly distributed patches of black and orange

• White underside due to dominant mutation of another gene

• Lyon hypothesis: A single X chromosome was inactivated in the cells of females

24

DOSAGE COMPENSATION• X chromosome inactivation

– Both coat color alleles are originally active

– One X chromosome is randomly inactivated in each cell during early embryonic development

– X inactivation is passed along to all future somatic cells during cell division

– Patches of cells with different coloration result

25

DOSAGE COMPENSATION• X chromosome inactivation

– DNA in inactivated X chromosomes becomes highly compacted

• A Barr body is formed

– Most genes cannot be expressed

26

DOSAGE COMPENSATIONDavidson, Nitowsky, and Childs (1963)

• Tested the Lyon hypothesis at the cellular level

• Analyzed expression of a human X-linked gene– Encoded the enzyme glucose-6-phosphate

dehydrogenase (G-6-PD)– Individuals vary with respect to this enzyme– Different alleles produce different yet functional

enzymes

27


• Variation in G-6-PD can be detected via gel electrophoresis– Electric current forces proteins through a gel– Different proteins different movement rates– Can discriminate between fast enzyme and slow

enzyme

28


• Hypothesis– Heterozygous adult females should express only one

enzyme in any particular somatic cell and its descendents

29

DOSAGE COMPENSATIONDavidson, et al. (1963)

• Experimental design– Isolate tissue from adult

heterozygote– Separate individual cells– Grow these cells in culture– Isolate proteins from various

clones– Subject proteins to electrophoresis

30

DOSAGE COMPENSATIONDavidson, et al. (1963)

• The data– A single form of the enzyme was

detected in each clone• Some clones produced the fast

enzyme

• Some clones produced the slow enzyme

31

DOSAGE COMPENSATIONDavidson, Nitowsky, and Childs (1963)• Interpreting the data

– Lane 1 contains a mixture of cells from a heterozygous woman

– Each clone produced only a single form of the enzyme

– The allele encoding the other form resides upon the inactivated X chromosome

– Consistent with the hypothesis

32

DOSAGE COMPENSATION• Genetic control of X inactivation

– Human cells (and those of other mammals) possess the ability to count their X chromosomes

– Only one is allowed to remain active• XX females 1 Barr body

• XY males 0 Barr bodies

• XO females 0 Barr bodies (Turner syndrome)

• XXX females 2 Barr bodies (Triple X syndrome)

• XXY males 1 Barr body (Kleinfelter syndrome)

33

DOSAGE COMPENSATION• Genetic control of X inactivation

– Not entirely understood– X-inactivation center (Xic) is involved

• Short region of the X chromosome

» Skip details

34

DOSAGE COMPENSATION• Genomic imprinting involves the physical

marking of a segment of DNA– Mark is retained and recognized throughout the life of

the organism inheriting the marked DNA– Resulting phenotypes display non-Mendelian

inheritance patterns– Offspring expresses one allele, not both– “Monoallelic expression”

35

DOSAGE COMPENSATION• Genomic imprinting

– The Igf-2 gene encodes an insulin-like growth factor• Functional allele required for normal size

• Igf-2m allele encodes a non-functional protein

– Imprinting results in the expression of the paternal allele only

• Paternal allele is transcribed

• Maternal allele is transcriptionally silent

36


– The Igf-2 gene encodes an insulin-like growth factor• Functional allele required for normal size• Igf-2m allele encodes a non-functional protein

– Igf-2m Igf-2m ♀ x Igf-2 Igf-2 ♂ • Normal offspring

– Igf-2m Igf-2m ♂ x Igf-2 Igf-2 ♀ • Dwarf offspring

– Different results in reciprocal crosses generally indicate sex-linked traits

• In this case, it indicates genomic imprinting of autosomal alleles

37


– The imprint of the Igf-2 gene is erased during gametogenesis

– A new imprint is then imparted• Oocytes possess an imprinted

gene that is silenced

• Sperm possess a gene that is not silenced

– The phenotypes of offspring are determined by the paternally derived allele

38


– Permanent in the somatic cells of an animal– Can be altered from generation to generation

39


– Occurs in several species• Numerous insects, plants, and mammals

– Effects can include• A single gene

• A part of a chromosome

• An entire chromosome

• All the chromosomes from one parent

40


– First discovered in the housefly Sciara coprophilia– These flies normally inherit three sex chromosomes

• One X chromosome from the female

• Two X chromosomes from the male

– Male flies lose both paternal X chromosomes during embryogenesis

– Female flies lose one paternal X chromosome during embryogenesis

41


– First discovered in the housefly Sciara coprophilia– The maternal X chromosome is never lost

• The maternal X chromosome is marked to promote its retention, or

• The paternal X chromosome is marked to promote its loss

42


– Can also be correlated with the process of X inactivation

– In some species, imprinting determines which X chromosome will be inactivated

• e.g., The paternal X chromosome is always inactivated in marsupials

• e.g., The paternal X chromosome is inactivated in extraembryonic tissue (e.g., the placenta) of placental mammals

– X inactivation is random in the placental embryo itself

43


– Involves the physical marking of DNA– Involves differentially methylated regions (DMRs)

located near imprinted genes• Maternal or paternal copy is methylated, not both

44


– Methylation occurs during gametogenesis

• Methylated in oocyte or sperm, not both

– This pattern of imprinting is maintained in the somatic cells of the offspring

– Imprinting is erased during gametogenesis in these offspring

• New imprinting established

45


– Methylation generally inhibits expression• Can enhance binding of transcription-inhibiting proteins

and/or inhibit binding of transcription-enhancing proteins

– Methylation can increase expression of some genes

46


– Identified in several mammalian genes– Biological significance is unclear– Plays a role in the inheritance of some human diseases

47

EXTRANUCLEAR INHERITANCE• Most genes are found in the cell’s nucleus

• Some genes are found outside of the nucleus– Some organelles possess genetic material– Resulting phenotypes display non-Mendelian

inheritance patterns• “Extranuclear inheritance”

• “Cytoplasmic inheritance”

48

EXTRANUCLEAR INHERITANCE• Mitochondria and chloroplasts possess DNA

– Circular chromosomes resemble smaller versions of bacterial chromosomes

– Located in the nucleoid region of the organelles• Multiple nucleoids often present

• Each can contain multiple copies of the chromosome

49

EXTRANUCLEAR INHERITANCE• Mitochondrial genome size varies greatly among

different species– 400-fold variation in mitochondrial chromosome size

• Mitochondrial genomes of animals tend to be fairly small

• Mitochondrial genomes of fungi, algae, and protists tend to be intermediate in size

• Mitochondrial genomes of plants tend to be fairly large

50

EXTRANUCLEAR INHERITANCE• Human mitochondrial DNA is called mtDNA

– Circular chromosome 17,000 base pairs in length• Less than 1% of a typical bacterial chromosome

– Carries relatively few genes• Genes encoding rRNA and tRNA

• 13 genes encoding proteins functioning in ATP generation via oxidative phosphorylation

51

EXTRANUCLEAR INHERITANCE• Most mitochondrial proteins are encoded by

genes in the cell’s nucleus– Proteins are synthesized in the cytosol and transported

into the mitochondria

52

EXTRANUCLEAR INHERITANCE• Chloroplast genomes tend to be larger than

mitochondrial genomes– Correspondingly greater number of genes– ~100,000 – 200,000 bp in length– Ten times larger than the mitochondrial genome of

animal cells

53

EXTRANUCLEAR INHERITANCE• Chloroplast DNA (cpDNA) of the tobacco plant

– 156,000 bp circular DNA molecule– 110 – 120 different genes

• rRNAs, tRNAs, and many proteins required for photosynthesis

• Many chloroplast proteins are encoded in the nucleus

54

EXTRANUCLEAR INHERITANCE• Most nuclear genes in diploid eukaryotes display

Mendelian inheritance patterns– Homologous chromosomes segregate during gamete

production– Offspring inherit one copy of each gene from each

parent

• The inheritance pattern of extranuclear genetic material displays non-Mendelian inheritance– Mitochondria and plastids do not segregate into

gametes as do nuclear chromosomes

55

EXTRANUCLEAR INHERITANCE• Pigmentation in Mirabilis jalapa

– The four-o’clock plant– Pigmentation is determined by chloroplast genes

• Green phenotype is the wild-type condition– Green pigment is formed

• White phenotype is due to a mutation in a chloroplast gene– Synthesis of green pigment is diminished

• Cells containing both types of chloroplasts display green coloration

– Normal chloroplasts produce pigment

– “Heterotroplasmy”

56


– Pigmentation in the offspring depends solely on the maternal parent

• “Maternal inheritance”

• Chloroplasts are inherited only through the cytoplasm of the egg

57


– Cells can contain both types of chloroplasts• Coloration is green because pigment is produced

– Chloroplasts are irregularly distributed to daughter cells during cell division

• Some cells may receive only chloroplasts defective in pigment synthesis

– The sector of the plant arising from such a cell will be white

• Variegated phenotype

58

EXTRANUCLEAR INHERITANCE• Studies in yeast and unicellular algae provided

genetic evidence for extranuclear inheritance of mitochondria and chloroplasts– e.g., Saccharomyces cerevisiae– e.g., Chlamydomonas reinhardtii

59

EXTRANUCLEAR INHERITANCE• Many organisms are heterogametic

– Two kinds of gametes are made• Female gamete tends to be large and provides most of the

cytoplasm to the zygote

• Male gamete is small and often provides little more than a nucleus

– Mitochondria and plastids are most often inherited from the maternal parent

60

EXTRANUCLEAR INHERITANCE• Many organisms are heterogametic

– Two kinds of gametes are made• Female gamete tends to be large and provides most of the

cytoplasm to the zygote• Male gamete is small and

often provides little more than a nucleus

– Mitochondria and plastids are most often inherited from the maternal parent

• Rarely, mitochondria are provided via the sperm

– “Paternal leakage”

61

EXTRANUCLEAR INHERITANCE• The inheritance pattern

of mitochondria and plastids varies among different species

62

EXTRANUCLEAR INHERITANCE• A few rare human diseases are caused by

mitochondrial mutations– Display a strict maternal

inheritance pattern

63

EXTRANUCLEAR INHERITANCE• Symbiosis involves a close relationship between

two species where at least one member benefits– Endosymbiosis involves such a relationship where

one organism lives inside the other

64

EXTRANUCLEAR INHERITANCE• Mitochondria and chloroplasts were once free-

living bacteria– Engulfed and retained

by early eukaryotes– Endosymbiosis

65

EXTRANUCLEAR INHERITANCE• Endosymbiosis

– Origin of chloroplasts proposed in 1883– Origin of mitochondria proposed in 1922– DNA was discovered in these organelles in the 1950s– Hotly debated topic when Lynn Margulis published

Origin of Eukaryotic Cells in 1970– Molecular analysis in the 1970s and 1980s provided

additional evidence– Endosymbiotic theory is currently virtually

universally accepted• Perhaps not among flat-earthers

66

EXTRANUCLEAR INHERITANCE• Plastids were derived from cyanobacteria

– Photosynthetic bacteria– Relationship allows

plants and algae to obtain energy from the sun

– Benefit to the bacterium is less clear

67

EXTRANUCLEAR INHERITANCE• Mitochondria were likely derived from gram-

negative nonsulfur purple bacteria– Relationship enabled

eukaryotes to produce larger amounts of ATP

68


– Most genes originally found in these bacterial genomes have been lost of transferred to the nucleus

• The DNA sequence of some nuclear genes indicates horizontal gene transfer from bacteria

– Biological benefits are unclear

69


– Transfer of mitochondrial genes to the nucleus has apparently ceased in animals

– Gene transfer from mitochondria and chloroplasts continues in plants at a low rate

– Transfer from the nucleus to the organelles has apparently almost never occurred

• One example in plants of transfer to the mitochondrion is known

70


– Horizontal gene transfer can also occur between organelles

• Between mitochondria

• Between chloroplasts

• Between a mitochondrion and a chloroplast

– Biological benefits are unclear

71

EXTRANUCLEAR INHERITANCE• Eukaryotic cells occasionally contain symbiotic

infective particles– Some individuals of the protozoan Paramecia aurelia

possess the “killer” trait• Secrete the toxin paramecin

• Many strains of paramecia are killed

72

EXTRANUCLEAR INHERITANCE• Killer strains contain cytoplasmic particles

– “Kappa particles”– 0.4 m long– Contain their own DNA

• Gene encodes paramecin toxin

• Genes encode resistance to this toxin

– Kappa particles are infectious• Particles in extract from killer strains can infect nonkiller

strains

• Converted to killer strains

73

EXTRANUCLEAR INHERITANCE• The protozoan Paramecia aurelia

– Some individuals possess the “killer” trait• Secrete the toxin paramecin

• Many strains of paramecia are killed

– Killer strains contain cytoplasmic particles• “Kappa particles”

• 0.4 m long

• Contain their own DNA– Gene encodes paramecin toxin

– Genes encode resistance to this toxin

74

EXTRANUCLEAR INHERITANCE• Eukaryotic cells occasionally contain symbiotic

infective particles– Certain strains of Drosophila possess a trait known as

sex ratio • Most of the offspring are female

– Most of the male offspring died

» Surviving males do not transmit the trait to their offspring

• Transmitted maternally

• Transmitted infective agent is a symbiotic microorganism

non men deli an

Documents