Gen y alelo: como diferenciarlos

Gen y alelo son conceptos se confunden a menudo. Aprender qué es un gen y qué es un alelo te permitirá prepararte para el siguiente paso en el estudio de la genética: comprender qué es la haplosuficiencia.

Alfonso Prado-Cabrero, PhD

Bebe con un subconjunto de cromosomas

Nuestra informacion geneticá esta duplicada

Cada ser humano hereda 23 cromosomas de su madre y 23 cromosomas de su padre. Así, al nacer, normalmente recibes 46 cromosomas  (Fig. 1). Como estos dos conjuntos de 23 cromosomas son esencialmente equivalentes, podemos emparejar cada cromosoma del padre con su cromosoma equivalente (u homólogo) de la madre. Homólogo significa que ambos cromosomas de cada pareja (generalmente) contienen los mismos genes y en las mismas posiciones. Podemos decir por tanto que recibimos nuestra información genética por duplicado. Sin embargo, existen muchas diferencias pequeñas entre cada par de cromosomas homólogos. Estas diferencias en la mayoría de los casos no arruinan nada; en cambio, son las responsables de hacernos más altos o más bajos, tener ojos azules o marrones. Las pocas veces que estas pequeñas diferencias toman relevancia es cuando causan que un gen no funcione, y esto puede provocar una enfermedad.

Figura 1. Representación de una niña con su madre (en fondo rosa), su padre (en fondo violeta) y los cromosomas que ha heredado de ellos. En rosa se representan los cromosomas que ha heredado de su madre y en violeta los cromosomas que ha heredado de su padre.

Si nos centramos en el primer par de cromosomas homólogos (Fig. 2), en su interior hay líneas negras de diferentes longitudes. Cada una de estas líneas simboliza un gen. Si observas este patrón en ambos cromosomas, es el mismo. Para enfatizar esta homología, muestro el nombre de los primeros cuatro genes.

Figura 2. Zoom del primer par de cromosomas homólogos. Las líneas negras de diferentes longitudes representan los genes que contiene cada cromosoma. Es de destacar que el patrón de líneas es el mismo en cada cromosoma. Se muestra el nombre de los primeros cuatro genes.

Ahora nos fijamos en uno de estos genes. Sus alelos tienen una pequeña diferencia…

Tomaremos el gen TBH como ejemplo. Este gen en realidad no existe, pero nos ayudará a comprender que son los alelos de un gen. La Figura 3 muestra la secuencia de ADN de los dos alelos del gen TBH que ha heredado la niña de la Figura 1. Hemos nombrado cada alelo siguiendo la nomenclatura utilizada en genética humana (TBH*1 y TBH*2). Si miramos la secuencia de ADN de cada alelo (la cadena con A, G, C y T), es idéntica en ambos casos, excepto por una adenina (A) en el alelo TBH*1 (distinguible por su tamaño de letra más grande), que es una guanina (G) en el alelo TBH*2. Este cambio es mínimo, y un cambio tan pequeño en la secuencia de un gen no suele tener consecuencias, pero a veces dicho cambio puede afectar la función del gen y, por tanto, la proteína que codifica.

Figure 3. DNA sequence of two alleles of the gene TBH. The different nucleotide in both alleles (A in the allele *1 anad G in the allele *2) can be distinguished by its larger font size.

Which implications such small difference may have?

As we know, the cell transcribes each allele into messenger RNA (mRNA), and then translates each mRNA into protein. Fig. 4 shows schematically the two alleles of the gene TBH of the girl of Fig. 1, highlighting the nucleotide that is different in both alleles (A in TBH*1 and G in TBH*2). The purpose of Fig. 4 is to show that the cell transcribes both alleles to mRNA normally, and then succesfully translates these mRNAs into protein. Nevertheless, if we look at the proteins produced by each allele, TBH*2 has a small bump (pointed by the arrow). This is the effect of the A and G difference: a single amino acid has changed, making the structure of the two proteins slightly different.

Figure 4. Schematic representation of the flow from gene to mRNA and protein for the two alleles of the TBH gene. These alleles have a deoxynucleotide which is different: A for TBH*1 and G for TBH*2. This difference is responsible for the subtle difference in structure of the resulting protein, pointed by the arrow.

What are the practical implications of such difference?

In this particular case, Fig. 5 shows these implications. TBH*1 can add a white ball to 20 black balls per second, and TBH*2 can do this to only 18 black balls per second. This is because the small bump highlighted in Fig. 4 in the protein TBH*2 is impairing to some extent the entrance of the substrate (black ball) into the protein. Researchers take the protein that works better (TBH*1) as reference, and say that this protein performs 100% activity. TBH*2 then works at 90% of possible activity.

Figure. 5. Performance of the proteins encoded by TBH*1 and TBH*2. The protein TBH*1 can convert 20 black balls into black and white balls per second. The protein TBH*2, instead, and due to the protuberance in its entrance, can conly process 18 black balls per second.

Are there only two alleles per gene?

No, usually there are more than two alleles of each gene. In the ficticious gene of our example, after a hard work, researchers have identified and characterized four alleles of TBH in the human population. In Fig. 7 we show the two remaining alleles.

If we look at TBH*3, we see that it looks like TBH*2, because it also has the G that makes the protein have a bump in its structure; but it has another change in sequence, consisting of an A in a position where TBH*1 and TBH*2 have another nucleotide. This change impairs transcription to mRNA of this allele, and therefore affects the number of proteins synthesized. This protein should have an activity of 90%, but in reality its activity is lower because there is less protein. Researchers have found that for the protein TBH*3, the bump plus the lower number of proteins yield a work which is 40% of the work that TBH*1 can do.

Figure 6. Alleles *3 and *4 of the TBH gene. The additional nucleotidic differences of these alleles over *1 and *2 have additional consequences at the protein level. For TBH*3, the additional difference makes DNA transcription into mRNA more difficult and therefore scarce. The consequence of this is a lower number of proteins produced. For TBH*4, the additional nucleotidic difference is not affecting transcription, but the mRNA produced contains an ‘end of translation’ signal, which makes the protein mostly incomplete and therefore useless.

The TBH*4 allele resembles TBH*1 because it has an A in the position we studied at the beginning, and its activity should be 100%. However, this allele contains another nucleotide change, which produces a change in its code that causes that when the mRNA is translated into protein, the ribosome finds a termination signal and releases the protein in construction, leaving it, therefore, unfinished. The synthesized protein is therefore useless, and its activity is, therefore, 0% when compared with the activity of TBH*1.

Who has these alleles of the TBH gene?

Fig. 8 is an example of how the alleles TBH*1, TBH*2, TBH*3 and TBH*4 are distributed in the population. If you want to learn about the implications of bearing different combinations of alleles of a gene, you can check out our post haplosufficiency and haploinsufficiency.

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