G is for Genome

Eduardo Orias
is a professor in UCSB’s Molecular, Cellular, and
Developmental Biology Department. He describes with great lucidity
the genetic realm, and he knows whereof he speaks: Late last year,
his team of researchers finished mapping an entire genome, that of
Tetrahymena thermophilia, a predatory protozoan of ancient
pedigree. Professor Orias’s decades-long study of this unicellular
organism has contributed to several major breakthroughs in the
understanding of human cells, because T. thermophilia
shares thousands of genes with Homo sapiens. The professor
responded with remarkable readability—especially for a scientist—to
a couple of sudden onslaughts of emailed questions from Martha
Sadler. In this barely edited transcript, Orias sheds a somewhat
disturbing light on our family ties to protozoa, genetic
engineering, sex, and death.

Could you make a giant protozoan by manipulating its

You might very well be able to, by learning what genes to
manipulate. (Perhaps we should propose a project to the Department
of Homeland Security.) Seriously, though, there probably is a limit
to how big you could make a Tetrahymena by manipulating
its genes. As a cell gets larger, volume scales as the cube and
surface area only scales as the square of the linear dimensions.
Thus the surface to volume ratio decreases; processes where surface
area is important (e.g. exchange of oxygen and waste gases) suffer
as a result of simple scaling up. Scaling could be viable if, for
example, you also manipulated genes to make the shape like that of
a long hollow cylinder of sheet metal, so no place inside the cell
would be far away from the surface. But then, the “makeover” would
have to be complex and many genes would have to be modified. In the
absence of a huge amount of knowledge, it would be nearly
impossible to accomplish this feat over calendar rather than
evolutionary time.

Could you make a cross between that protozoan and a

This certainly is an imaginative question! I assume that you
mean creating an organism with half of its genes derived from
Tetrahymena and half from a cat. I would say that
the odds against this happening without human intervention are
unimaginably high. But you might imagine experimental manipulation
that could introduce all the Tetrahymena chromosomes into
the nucleus of a cat egg or all the cat chromosomes into the
germline nucleus of Tetrahymena. This manipulation seems
feasible but …would the product survive? I don’t know; I am not
aware that anyone has tried it. However, I would bet it wouldn’t —
and in making this bet I would not think that I was gambling at
all. The genes for the proteins that support many functions that
are important for animals have been lost or their sequence has
evolved beyond recognition in Tetrahymena. Likewise for
the reciprocal case. Even the many proteins that are recognizably
similar in both organisms have mutated, over 2-3 billion years of
independent evolution, enough that most of them would probably be
unable to interact efficiently with one another. It would be like
trying to construct a smoothly operating vehicle that incorporated
all the parts from a car and all the parts from a submarine. A more
modest but very useful goal has been achieved, namely the use of
Tetrahymena cells as a “factory” for the high level
production of individual, valuable proteins from humans or other
organisms, by introducing the relevant genes into the
Tetrahymena cells. Is it true that mitochondria
was once a separate organism that got incorporated into the human
organism and never left? Like a very close symbiotic or parasitic

The basic idea is correct; the mitochondria were once bacteria
that were taken in by a “proto-eukaryote”, and established a very
intimate endosymbiotic relationship. Eukaryotes are organisms that
have a true nucleus, as distinct from bacteria, which lack a
nucleus. Today, our mitochondria are essential for the production
of energy using oxygen. Because the mitochondrion still conserves
DNA inherited from its ancestors, we know exactly what group of
bacteria the original endosymbiont belonged to. What is not right
is the suggestion that it was a human organism that established the
relationship. Rather it was a human ancestor, who lived so long ago
that this ancestor was still a unicellular organism
(protozoan-like). Indeed, this endosymbiotic relationship is
estimated to have started more than 2-3 billion years ago,
i.e. earlier that half the life of the solar system!

A press release from the university says that “thousands of
genes are shared by the protozoan Tetrahymena thermophila
and humans.” What characteristics do we have in common?

We have in common characteristics in all major processes of cell
biology. The genes for these processes are shared by descent from a
common ancestor. The gene sequences are conserved (i.e., remain
very similar) because Tetrahymena and we are free living,
animal-like organisms that have maintained similar cell biology.
The functions of the conserved genes are very important and natural
selection (in Tetrahymena and in us) has weeded out
mutations that would significantly affect that function.

In article published recently in Scientific
American posited that natural aging and death will be
genetically defeated within the next 30 years given the exponential
advances in genetic engineering. Could we be the last generation of

I’ll bet you a lunch that the prediction is wrong! But if I’m
the one who has to pay, it may well be in a coffee house in
Paradise because by then our respective well-meaning friends may
have had to do us in, in order to make room for the young.

Is it your understanding that fraying at the tips of
chromosomes is responsible for natural aging and

The specialized DNA sequence at the tip pf chromosomes is known
as the telomere. They serve a number of functions, a critical one
being the protection of the inner sequence of the chromosome (a
crude analogy would be the reinforcement at the tip of shoelaces).
Perhaps you have read that the fundamental knowledge about the
structure of telomeres and how they are maintained was discovered
in Tetrahymena. Following up on these studies, it was then
discovered that humans (and many other eukaryotes) use the same
biology to protect chromosome ends. The relevance to aging and
cancer derived from the fact that most types of cells in our body
are not expressing the enzyme that maintains telomeres (known as
the telomerase). In the absence of telomerase, telomeres get
shorter at every cell division. The older we get, the more
divisions the cells in certain tissues have to undergo, and they
may begin running out of telomere sequence. As chromosomes get
shorter, cells sense the problem and stop dividing or die. The
relevance to cancer comes because cancer cells are cells with a
mutation that inactivates cell division controls and undergo
run-away division. If they are not expressing telomerase, sooner or
later they run out of telomeres; then they stop dividing or die and
the cancer does not get established. (Successful cancer cells need
additional mutations that cause the expression of the telomerase
gene, or which generate a different way to maintain telomeres.)

Are we more closely related to Tetrahymena than
to other protozoa?

We are more closely related to some other protozoa; those
protozoa and humans are equally distantly related to
Tetrahymena. Still other protozoa are more closely related
to Tetrahymena than to humans, while others are equally
distant from humans and Tetrahymena because they are at
the end of a separate branch from that of humans and
Tetrahymena. In fact, most of the biodiversity on Earth
resides in unicellular organisms.

Are more closely related to this “tiny predatory
protozoan” than we are to some mammals?

We humans are very closely related to all living mammals; all
living mammals are equally distantly related to
Tetrahymena. Think of an imaginary tree in which all the
leaves are at the same distance (as a caterpillar would measure it)
from the place where the primary branching occurs. The distance
between a human and say a mouse is analogous to the total distance
that a caterpillar would have to travel to get from the “human
leaf” to the “mouse leaf”. Since that branching occurred near the
tip of our branch, the distance is small. To travel from the human
leaf to the Tetrahymena leaf the caterpillar would have to
go way back to the primary branching and travel along a different
primary branch. That distance is much longer.

If not, are we more closely related to it than we are to
a fish?

The branching with the fish (which are vertebrates but not
mammals) occurred further back that the mouse branch, but is still
much closer than the primary branch. Thus we are much more closely
related to fish than we are to Tetrahymena. Tetrahymena is
equally distantly related to fish and humans.

The press release makes the dubious claim that
Tetrahymena has 27,000 genes, “a number remarkably similar
to the number of genes found in the human genome.” Does that mean
that the protozoan might be as complex as humans?

At the cell biology levels, Tetrahymena and humans are
equally complex in terms of the structures and processes that take
place within them. Humans are more complex in the sense that they
have a variety of cell types that differentiate from the fertilized
egg (e.g., blood cells, skin cells brain cells, etc.), while
Tetrahymenass essentially possess just one cell type. One
way that the added complexity is achieved in humans and other
mammals is by making different proteins from the same gene, by
cutting and splicing the messenger RNA sequence in different ways
in different tissues or in different circumstances. (The messenger
RNA is essentially a working copy of the DNA gene sequence and it
is used to synthesize the proteins; because it is a copy, the gene
sequence itself is not altered by the cutting and splicing.) P.S.:
Why do you say “dubious”? Numbers are numbers.

Dubious because it seems odd that a unicellular organism
would have as many genes as moi.

Oh, I understand now. With about the same number of genes, we
generate a greater diversity of unique proteins by cutting and
splicing the messenger RNAs. I hope this reassures “moi” as much as
it does me.

Can one gene carry a greater quantity of information
than another?

In principle, more information can be encoded in a longer gene
than in a shorter gene, just as more information can be encoded in
a longer written message than in a shorter one. But, just as in the
written message analogy, it also depends on how concisely the
information is encoded.

Do we carry around many genes that are not

Not every gene is expressed at the same time–or in the same
cells in the case of multicellular organisms. The level of
expression of a gene is very often responsive to environmental
circumstances. For example, the presence of heavy metals in the
growth medium causes an increase in the level of expression of
proteins that can sequester the heavy metal so it causes no harm to
other important proteins in the cell. Cells have evolved to be
prudent and efficient in the use of their resources, and that
includes what genes are expressed under what circumstances.

For how long do unexpressed genes get carried around:
one generation, two, 100?

I would suggest more than 1000. A gene that is unexpressed under
any circumstances in an organism that grows and reproduces normally
would have to be a useless gene. All genes are constantly subject
to random mutation, which are more likely than not to be
deleterious. (In any complex machinery, there are always many more
ways to make random changes in it that will make it work worse
rather than better.) If a gene is of no use, there is no natural
selection to eliminate its mutations, thus no tendency for the
original version to survive preferentially. Thus the sequence of a
useless gene changes in a random way with evolutionary time.
However, it would probably take in the order of thousands of sexual
generations to obliterate detectable similarity to the ancestral

Do recessive characteristics eventually disappear from a
gene pool if people interbreed with those who have dominant

No, there is no tendency for loss as a consequence of
interbreeding just because one form of the gene is dominant or
recessive compared to another form of the gene. On average, in a
large population, the frequency of homozygotes (e.g., AA or aa) or
heterozygotes (Aa) tend to remain constant in the absence of
natural selection for any given version. Do men and women
have the same number of genes?

The Y chromosome has much fewer genes than the X chromosome.
Thus, numerically, women have more genes that men because women
have XX sex chromosome composition, while men have XY. In terms of
distinct genes, men have more, because the Y chromosome has
different genes than the X chromosomes. In all other 22 human
chromosome pairs, the two members have the same genes.

Is it true that all babies start as females and if
stressed they become male?

Not in humans. Sex is strictly determined by sex chromosome
make-up, which in turn depends on whether the sperm brought in an X
or a Y chromosome. In some animals, the mechanism of sex
determination allows sex to be influenced by environmental
conditions, like temperature.

Do your protozoa have X and Y chromosomes?

The equivalent of sexes is found in protozoa, and they are
called “mating types” because generally there is no shape
difference associated with different mating types. Having two
mating types is common among many protozoan species.
Tetrahymena thermophila is unusual in having seven mating
types. A cell of one mating type can mate with a cell of any mating
type except its own: Molecules on the surface of the cell of one
mating type can react with complementary molecules on the surface
of another cell of the same species and signal whether or not their
mating types are different. The discoverer of the seven
Tetrahymena mating types, David L. Nanney, could have
coined a family of seven names, seeded by the words “male,”
“female,” and so on. Instead he chose to assign Roman numerals to
the mating types.

Do they evolve very quickly? How long have they been

Rates of DNA change can be directly calibrated only in organisms
(uni- or multicellular) whose remains can become fossilized, like
bone- or shell- or wood-containing organisms. Tetrahymenas
are entirely made of “soft” parts, and their ancestors have not
left any fossils that anybody has recognized yet. On the other
hand, and also by comparing related species, we can conclude that
the external appearance of the organism has not changed appreciably
over recent evolutionary time. It would not surprise me if cells
that look like contemporary Tetrahymenas have been around
for more than 10 million, and perhaps 100 million years. So
Tetrahymena appears to behave similarly to certain
animals, like cockroaches, that have been very successful but have
not changed much in appearance over long evolutionary times, which
are often dubbed “living fossils”.

How much do individual Tetrahymena thermophila
differ from one another?

On a purely visual level, to us humans looking through a
microscope, they all look about the same but they are basically as
similar and dissimilar from one another as humans at the DNA
sequence level. (In humans, the fraction of DNA “letters” that are
different from one individual to another is about three million, or
about 0.1 percent. In Tetrahymena the fraction is not well
established.) Tetrahymenas have physiological mechanisms
that help them avoid inbreeding and thus distribute more widely any
genetic diversity present in the population. We humans also avoid
inbreeding, but the mechanisms are largely cultural rather than

How many species’ genomes have been mapped

Hundreds of genomes have been sequenced to various degrees of
completion. The majority are bacterial genomes, which are small and
thus inexpensive to sequence. In addition, most of the major
eukaryotic model organisms (i.e., organisms on which it is easy and
less expensive to do research that illuminates the biology of all
organisms) have now been sequenced. The cost of sequencing has been
decreasing rapidly and the day may come when anyone can afford to
have his/her own genome sequenced.

Here is a question for you that my wife reminded me about: How
do you tell the sex of a chromosome?

I don’t know. How?

Pull down its genes.


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