Homeotic Homeotic mutationsmutations

We know some misterious mutations, which We know some misterious mutations, which generate horroristic monstersgenerate horroristic monsters

The homeosis

• Mutation, that causes transformation of an area of the body into another area

• The mutated genes the so-called Homeobox genes, shortly Hox genes

Products of Hox genes

• The Hox genes contain a 180 bp conservated region: the homeobox

• The homeobox encodes a 60 AA length homeodomain = a DNA-binding helix turn helix motif

• The homeodomain proteins are transcription factors• The Hox genes are selector genes (regulate the

expression of other so-called realisator genes)• The expression of several Hox genes is region-

specific in the embryo

• The homeotic transformations got known first in Drosophyla

• The regulation of Hox expression and the role of Hox genes is well known in Drosophyla

Hierarchy of genes in Drosophila development

Realisator genes

Maternal factor

Pair rule genes

Gap genes

Development of the number of segments

Development of the features of the segments

Selector genes (Selector genes (HoxHox genes) genes)

Hierarchy of genes in Drosophila development

bicoid (maternal factor)

hunchback (gap gene)giant (gap gene)

Krüppel (gap gene)

Organization of Organization of DrosophilaDrosophila HoxHox genesgenes

AntennapediaAntennapedia complex complex BithoraxBithorax complex complex

HOM-C complexHOM-C complex

3’5’

The pattern of The pattern of HoxHox expression expression

labialproboscipedia

deformed

Sex comb reduced

Antennapedia

Ultrabithorax

Abdominal A

Abdominal B

3’5’

The pattern of The pattern of HoxHox expression expression

• ColinearityColinearity between between the order of the the order of the HoxHox genes and the genes and the expression pattern expression pattern along the A/P axis, for along the A/P axis, for example:example:– in the first position of in the first position of

the HOM-C comlex is the HOM-C comlex is the the labiallabial, and it has , and it has the most anterior the most anterior expression.expression.

The pattern of The pattern of HoxHox expression expression– the first the first lablab is expressed alone is expressed alone

– the second the second pbpb is expressed with is expressed with lab, lab, etc.etc.

– the last the last Abd-BAbd-B is expressed with is expressed with all the othersall the others

– there aren’t wings, or legs on the there aren’t wings, or legs on the abdomen –WHY??abdomen –WHY??

– The more posterior Hox gene The more posterior Hox gene supresses the affect of more supresses the affect of more anterioranterior

– For example: For example: UbxUbx, , AbdAAbdA and and AbdBAbdB supresses the development supresses the development of the legsof the legs

Elucidation of Antennapedia Elucidation of Antennapedia phenotypephenotype

• There are legs in the place of antennaeThere are legs in the place of antennae• This segment of the head looks like a This segment of the head looks like a

thoracal segmentthoracal segment• Normally, the Normally, the AntpAntp isn’t expressed in the isn’t expressed in the

headhead• Gain of function mutation of Gain of function mutation of AntpAntp causes causes

abnormal abnormal AntpAntp expression in the head expression in the head • The more posterior The more posterior HoxHox gene dominates gene dominates

above the more anteriorabove the more anterior• AntpAntp transforms the head segment into transforms the head segment into

thoracal segment!!!thoracal segment!!!

What are the animals?• An animal is an organism that displays a particular

spatial pattern of gene expression. This pattern is the zootype.

• Every animal use the same regulation method to the developing of very different structures

lblbpbpb

DfdDfdUbxUbx

AbdBAbdB

eveeve

otdotd

emsems

ScrScr

Mammalian Mammalian HoxHox genes genes

• In mice and human 4 In mice and human 4 HoxHox clusters have clusters have been found been found

• Homology has been found between the Homology has been found between the DrosophylaDrosophyla and human and human HoxHox genes genes

DrosophylaDrosophyla and human Hox genes and human Hox genes

4 clusters:4 clusters: Hox A: Chr. 16Hox A: Chr. 16 Hox B: Chr. 11Hox B: Chr. 11 Hox C: Chr 15Hox C: Chr 15 Hox D: Chr. 2Hox D: Chr. 2

13 paralog groups13 paralog groups

38 Hox genes38 Hox genes

Archetypal organisation of Archetypal organisation of AmphioxusAmphioxus HoxHox gene cluster gene clusterJordi Garcia-Fernandez & Peter Jordi Garcia-Fernandez & Peter W. H. HollandW. H. Holland

Nature, 1994, vol. 370Nature, 1994, vol. 370

The evolution of the The evolution of the HoxHox clustersclusters

The evolution of the The evolution of the HoxHox clusters clusters

• The changes in The changes in HoxHox gene number gene number and genomic organization played and genomic organization played an important role in metazoan an important role in metazoan body-plan evolutionbody-plan evolution

• Garcia-Fernandez and Holland Garcia-Fernandez and Holland examined the organisation of examined the organisation of HoxHox genes in cephalochordate genes in cephalochordate AmphioxusAmphioxus (Brachiostomata (Brachiostomata floridae)floridae)

The The AmphioxusAmphioxus HoxHox gene cluster gene cluster

• The The AmphioxusAmphioxus genome has only one genome has only one HoxHox clustercluster

• It contains homologues of the mammalian It contains homologues of the mammalian HoxHox genesgenes

Relationship of the Amphioxus and mammalian Hox genes

• The sequence of homeobox of 10 Amphioxus Hox genes have been analised

• It has been compared with members of mammalian paralog groups

• Conservative amino-acid residues have been found

Evolution of Hox gene cluster

Hypothetical common ancestor

Amphioxus

Evolution of Hox gene clusterVertebrata genome contains 4 Hox clusters, Vertebrata genome contains 4 Hox clusters, DrosophylaDrosophyla genome contains only one genome contains only one

In general: we can see one-to-four relationship In general: we can see one-to-four relationship between invertebrate and vertebrate gene between invertebrate and vertebrate gene number (for example insulin receptor, notch …)number (for example insulin receptor, notch …)

Two genome duplications happenedTwo genome duplications happened

The Cambrian explosionThe Cambrian explosion

• Nearly all the extant phyla of kingdom Nearly all the extant phyla of kingdom Animalia emerged within few tens of Animalia emerged within few tens of million yearsmillion years

• This evolutionary explosion started about This evolutionary explosion started about 530 million years ago530 million years ago

• The assumed cause of it the genome The assumed cause of it the genome duplicationduplication

The genome duplications

The genome duplications

• Larger Larger HoxHox gene number gene number

More complicated body patternMore complicated body pattern