The intron–exon architecture of many eukaryotic genes raises the intriguing question of whether this unique organization serves any function, or is it simply a result of the spread of functionless introns in eukaryotic genomes. In this review, we show that introns in contemporary species fulfill a broad spectrum of functions, and are involved in virtually every step of mRNA processing. We propose that this great diversity of intronic functions supports the notion that introns were indeed selfish elements in early eukaryotes, but then independently gained numerous functions in different eukaryotic lineages. We suggest a novel criterion of evolutionary conservation, dubbed intron positional conservation, which can identify functional introns.

reast cancer is the second leading cause of cancer-related deaths and the most commonly diagnosed cancer in women across the world (1). Digital mammography (DM) is the primary imaging modality of breast cancer screening in women who are asymptomatic. In a diagnostic workup setting (2), DM has been shown to reduce breast cancer mortality (3). In standard clinical practice, a radiologist reads mammograms and classifies the findings according to the American College of Radiology (4) Breast Imaging Reporting and Data System (BI-RADS) lexicon. An abnormal finding depicted at DM typically requires a diagnostic workup, which may include additional mammographic views or possibly additional imaging modalities. If a lesion is suspicious for cancer, further evaluation with a biopsy is recommended. Analyzing these images is challenging because of the subtle differences between lesions and background fibroglandular tissue, different lesion types, the nonrigid nature of the breast, and the relatively small proportion of cancers in a screening population of women at average risk (2). This leads to substantial intraobserver and interobserver variability (5). The average performance measures for screening mammography by a radiologist was reported by Lehman et al (6) to be 86.9% sensitivity and 88.9% specificity. Breast cancer risk prediction models on the basis of clinical features can help physicians estimate the probability of an individual or population to develop breast cancer within certain time frames. As a result, they are often used to recommend an individual screening plan. In a systematic survey of risk prediction models, Meads et al (7) reported a limited performance when applied to general populations (area under the receiver operating characteristic curve [AUC], 0.67; 95% confidence interval [CI]: 0.65, 0.68), and showed improved results when applied to high-risk populations (AUC, 0.76; 95% CI: 0.70, 0.82).

An appreciable fraction of introns is thought to have some function, but there is no obvious way to predict which specific intron is likely to be functional. We hypothesize that functional introns experience a different selection regime than non-functional ones and will therefore show distinct evolutionary histories. In particular, we expect functional introns to be more resistant to loss, and that this would be reflected in high conservation of their position with respect to the coding sequence. To test this hypothesis, we focused on introns whose function comes about from microRNAs and snoRNAs that are embedded within their sequence. We built a data set of orthologous genes across 28 eukaryotic species, reconstructed the evolutionary histories of their introns and compared functional introns with the rest of the introns. We found that, indeed, the position of microRNA- and snoRNA-bearing introns is significantly more conserved. In addition, we found that both families of RNA genes settled within introns early during metazoan evolution. We identified several easily computable intronic properties that can be used to detect functional introns in general, thereby suggesting a new strategy to pinpoint non-coding cellular functions.