A nuclear gene is a gene whose DNA sequence is located within the cell nucleus of a eukaryotic organism. These genes are distinguished from extranuclear genes, such as those found in the genomes of mitochondria and chloroplasts, which reside outside the nucleus in their own organellar DNA. Nuclear genes encode the majority of proteins and functional RNAs required for cellular processes, including development, metabolism, and regulation.

Unlike the small, circular genomes of mitochondria and chloroplasts, nuclear genes are organized into linear chromosomes and are typically inherited in a Mendelian fashion, following the laws of segregation and independent assortment. In contrast, extranuclear genes often exhibit non-Mendelian inheritance, such as maternal inheritance in mitochondrial DNA.

While the vast majority of eukaryotic genes are nuclear, exceptions exist in certain protists and algae, where some genes have migrated from organelles to the nucleus over evolutionary time through endosymbiotic gene transfer. The study of nuclear genes is fundamental to genetics, molecular biology, and biotechnology, as they play a central role in gene expression, heredity, and genetic engineering.

The study of nuclear genes traces all the way back to the discovery of the nucleus in the 19th century, but the evolutionary origin of nuclear genes became clearer with the advances within molecular biology. Early work by Lynn Margulis in the 1960s proposed that mitochondria descended from free-living bacteria engulfed by a host cell, a process called endosymbiosis. This theory explains a process called endosymbiotic gene transfer which is how many genes from these endosymbionts were transferred to the host's nuclear genome over time.

Further research later revealed that nuclear genes have a mosaic ancestry which means that while some nuclear genes derive from the mitochondrial or bacterial ancestors, others will trace back to an archaeal host or arise as eukaryotic innovations. Carl Woese’s three-domain system, written in 1977, reinforced this view by showing the eukaryotes’ deep evolutionary ties to archaea. Today, nuclear genes are understood to be a composite of archaeal, bacterial, and uniquely eukaryotic elements, reflecting the complex history of the eukaryotic cell.

Nuclear genes play a central role in nearly all aspects of eukaryotic biology, encoding the majority of proteins and regulatory RNAs necessary for cellular function. Unlike organellar genes (e.g., mitochondrial or chloroplast DNA), which are limited to a small number of metabolic and energy-related processes, nuclear genes govern development, growth, reproduction, and homeostasis. They are transcribed in the nucleus and often translated in the cytoplasm, with their products directed to various organelles, including mitochondria and chloroplasts, through specialized signaling sequences.

The regulation of nuclear genes is highly complex, involving mechanisms such as transcription factors, epigenetic modifications, and non-coding RNAs. This allows for precise control over gene expression in response to environmental signals, cellular stress, or developmental stages.

For example, homeobox genes—a critical class of nuclear genes—orchestrate body plan development in animals, while nuclear-encoded photosynthesis genes in plants regulate chloroplast function. Nuclear genes are also of paramount importance in medicine and biotechnology. Mutations in these genes are linked to thousands of genetic disorders, including cancers, metabolic syndromes, and neurodegenerative diseases. Additionally, nuclear genes are primary targets for genetic engineering—CRISPR-Cas9 and other gene-editing technologies predominantly modify nuclear DNA to study gene function or develop therapies.