Evolving Concepts: The Role of Gene Loss in Animal Evolution

Edward M. De RobertisHHMI/UCLA, USA

Animal evolution used an ancestral “genome tool-kit” shared by all bilateral animals.

1) Whole-genome duplications followed by massive gene loss were very important evolutionary events.

2) Gene deletions are common, but limit future evolutionary change.

3) Similar functions can be fulfilled by very different genes – the case of self-avoidance in neurons.

Slide 1

Genomes contain the record of our evolutionary history

Ur = Primeval Bilateria = all bilateral animals (30 phyla) Slide 2

The common ancestor Urbilateria used conserved systems of developmental control genes.

BMP

Chd

Hox

De Robertis & Sasai, Nature 1996Slide 3

De Robertis, Cell 2008

The Chordin/BMP network patterns D-V differentiation in vertebrates, Drosophila, and many other animals.

Slide 4

Platypus

Higher Mammals

Fish, amphibians, reptiles and birds have a conserved Dorsal-Ventral regulatory system

Slide 5

Homeotic genes specify A-P segment identity in Drosophila. Colinearity between their order in DNA and in the body.

Edward B. Lewis

Walter J. Gehring

Slide 6

“A Xenopus laevis gene was cloned on the basis of cross-homology to a region conserved between several Drosophila homeotic genes… This gene could perhaps represent the first development-controlling gene identified in vertebrates.”

Carrasco, McGinnis, Gehring and De Robertis, Cell 1984

Homeobox DNA encodes a DNA-binding protein domain of 60 amino acids called the Homeodomain.

Slide 7

P. Holland, WIREs Dev. Biol. 2, 31-45 (2013)

Hox gene complexes

Slide 8

P. Holland, WIREs Dev. Biol. 2, 31-45 (2013)

Urbilateria

DeuterostomesEcdysozoa

Whole-genome duplications

Slide 9

Susumu Ohno published the prescient book “Evolution by Gene Duplication” in 1970.

Using cytogenetics and DNA quantification methods he predicted that two whole-genome duplication events had occurred during vertebrate evolution.

He also predicted that bony fishes would be 8X, and that the surf smelt (8X), trout (16X) and salmon (32X) were a polyploid series.

He realized that duplications gave the opportunity for two genes to adopt different function or regulation.

The role of gene deletion is less generally recognized.

Slide 10

For each duplication there is an accompanying deletion.

Tandem duplications in DNA occur readily by unequal crossing over

Slide 11

Nature 453, 1064-1071 (2008)

Comparison of the amphioxus genome to the human genome showed that 25% of human genes retained 2 or more copies. Thus, a process of massive gene loss left humans with 75% of our protein-coding genes as single copy.

Slide 12

Homeobox transcription factor loss in chordates.

Holland et al. Genome Res. 18, 1100-1111 (2008)

Chordate ancestor560 Mya

Ascidians lost 2,250 gene families present both in amphioxus and humans

Slide 13

Baker’s yeast (Saccharomyces cerevisiae) underwent an ancient whole-genome duplication followed by massive gene deletions of 88% of the duplicated genes. The 12% that remained duplicated have diverged in sequence and function.

Slide 14

In vampire bats a change in feeding habit led to a very thin esophagus and can no longer feed on insects.

Laboratory mice reproduce throughout the year, instead of seasonally. Caused by mutations in two enzymes that synthesize melatonin from serotonin in the pineal gland.

Loss-of-function represents a common response to changes in the environment or in habits

Flightless birds and beetles. Darwin described that in the windy island of Madeira of 550 beetle species 200 have become flightless.

kiwi

Slide 15

Sticklebacks are marine fish that spawn in fresh water. They became trapped in lakes 10,000 years ago after the last ice age. They represent

very recent, and repeated, natural evolutionary experiments.

Slide 16

Why would sticklebacks ever lose the pelvis?

• Shallow lakes often contain insect predators that grasp spines

(After Reimchen, 1980)

Sticklebacks have lost the pelvic spines independently in diverse populations

Slide 17

Pelvic spine loss occurred by multiple independent deletions of an enhancer DNA region required for Pitx1 gene expression in the pelvis. (Work of David Kingsley.)

Ectodysplasin mutations cause loss of armored plates but this mutation was present in the marine population. Slide 18

Urbilateria: a complex or simple animal?

Slide 19

The notochord is a flexible rod used for swimming in the chordates

Slide 20

Slide 21

Detlev Arendt et al., Science 2014

The notochord of the chordate amphioxus is also muscular but the contractile nature was lost when the vertebrate notochord became a flexible rod.

Slide 22

Generating diversity: “Nature is very inventive”.

Self- avoidance in neuronal circuits is mediated by Dscam in Drosophila and by protocadherins in mammals.

Slide 23

Self-avoidance is essential for neurons to form the proper circuits. Mutation of Dscam1 (Down syndrome cell adhesion molecule) gene in Drosophila eliminates repulsion between branches of the same neuron.

Larry Zipursky Slide 24

Zipursky and Sanes, Cell 143, 343-353 (2010)

Drosophila uses alternative splicing of mRNA to generate many Dscam proteins. 12 x 48 x 33 x 2 = 38,016 different proteins from one gene. Fruit flies have 15,000 genes and humans about 20,000 protein-coding genes.

Only when the three variable Ig domains match each other the extracellular domains recognize each other and they stimulate repulsion via the cytoskeleton. Each neuron is unique because it expresses 10-20 Dscam1s stochastically

Slide 25

Tom Maniatis et al., Nature 2012

In mice and men clustered protocadherin genes use alternative promoters to express the proteins stochastically in neurons. Homophilic binding of tetrameric proteins triggers repulsion and self-avoidance but using a completely different transmembrane protein.

Slide 26

"Only if the Redeemer is also Creator can he really be Redeemer. That is why the question of what we do is decided by the ground of what we are. We can win the future only if we do not lose creation."

Monod proposed a new “ethics of knowledge” with the main guiding principle being the principle of objectivity. In the end it was a dark message:

“The ancient covenant is in pieces; man knows at last that he is alone in the universe’s unfeeling immensity, out of which he emerged only by chance.”Chance and Necessity, p. 180, 1972.

F. Jacob took a more optimistic view:

“Western science is founded on the monastic doctrine of an orderly universe founded by God who stands outside of nature and controls it through laws accessible to human reason”. The Possible and the Actual, p. 10, 1982.

A stronger response came from the Frauenkirche in Munich:

Slide 27

"Only if the Redeemer is also Creator can he really be Redeemer. That is why the question of what we do is decided by the ground of what we are. We can win the future only if we do not lose creation."

Similar views are held by Pope Francis: In fact, the Pope explained, “God made things — each one — and he let them go with the interior, inward laws which he gave to each one, so that they would develop, so they would reach fullness.”

Slide 28

In sum, animals evolved through variations in ancestral developmental gene networks in our DNA. It seems a miracle that we humans got to where we are today through evolutionary gains and losses of an ancient set of animal genes.

Slide 29

Conclusions:

Animals derive from a conserved animal genomic tool-kit.

1) Developmental control networks placed evolutionary constraints on the animal anatomies that evolved by natural selection. The results of evolution are dependent on constraints imposed by our previous history.

2) Genome-wide duplications followed by copious deletions facilitated adaptations in the course of evolution.

3) Genes that are no longer needed are rapidly deleted but this causes loss of potential to evolve.

4) Very different genes can be used to achieve the same physiological needs.

Slide 30